Construction of anti-1,2-diols bearing chiral tertiary alcohol moiety using free hydroxyacetone as aldol donor by imidazole-based prolineamide catalyst

Article abstract of DOI:10.1016/j.tet.2014.07.015

A direct aldol reaction of free hydroxyacetone and activated ketone has been firstly achieved with a newly developed imidazole-based prolineamide catalyst. The adducts anti-1,2-diols bearing a chiral tertiary alcohol moiety were obtained in high yield (up to 92%) and stereoselectivity (up to 15:1 dr and 90% ee).

Full text of DOI:10.1016/j.tet.2014.07.015

Tetrahedron 70 (2014) 6561e6568
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Construction of anti-1,2-diols bearing chiral tertiary alcohol moiety
using free hydroxyacetone as aldol donor by imidazole-based
prolineamide catalyst
,
,
a,
Wengang Guo a b, Jianwei Wei a, Yan Liu a , Can Li
*
*
a State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
b Graduate School of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 May 2014
Received in revised form 28 June 2014
Accepted 2 July 2014
Available online 7 July 2014
A direct aldol reaction of free hydroxyacetone and activated ketone has been firstly achieved with
a newly developed imidazole-based prolineamide catalyst. The adducts anti-1,2-diols bearing a chiral
tertiary alcohol moiety were obtained in high yield (up to 92%) and stereoselectivity (up to 15:1 dr and
90% ee).
Ó 2014 Published by Elsevier Ltd.
Keywords:
Imidazole
Organocatalyst
Hydroxyacetone
Asymmetric
Aldol reaction
1. Introduction
reaction of hydroxyacetone, to our surprise, the aldol acceptors
are still limited to aldehydes or aldimines7 (Eqs. 1 and 2, Scheme 1).
Hydroxyacetone is a cheap and easily available chemical feed-
stock and widely used as starting material in the synthetic chem-
istry.1 The asymmetric 1,2-addition reaction using hydroxyacetone
as a donor received much attention because of their potential
synthetical usefulness for constructing chiral 1,2-diols and 1,2-
amino alcohols, which represent privileged structures commonly
found in a vast array of bioactive natural products and synthetic
compounds of medicinal interest.2 Since the first report of List
about the organocatalytic aldol reaction between hydroxyacetone
and aldehydes to give anti-diols in the presence of proline,3 there
has been extensive efforts devoted to controlling the selectivity and
extending the substrate scopes with various organocatalysts. In
2002, Barbas and co-workers reported for the first time a proline-
Thus, the development of catalytic protocols utilizing ketones as
electrophilic partners with hydroxyacetone to construct 1,2-diols
still remains a distinct challenge (Eq 3, Scheme 1).
catalyzed 1,2-addition of hydroxyacetone with
a-imino glyox-
ylate.4 Several years later, their group and others achieved the anti-
Mannich-type and syn-Aldol reactions of hydroxyacetone by using
primary amine as catalysts.5 Gong and co-workers reported the
asymmetric direct aldol reactions of hydroxyacetone with alde-
hydes to prepare 1,4-diols by using the small peptides as efficient
catalysts.6 Despite of these elegant successes in the 1,2-addition
* Corresponding authors. Tel.: þ86 411 84379070; fax: þ86 411 84694447; e-mail
Scheme 1. Enamine catalysis for the 1,2-addition of hydroxyacetone.
addresses: yanliu503@dicp.ac.cn (Y. Liu), canli@dicp.ac.cn (C. Li).
http://dx.doi.org/10.1016/j.tet.2014.07.015
0040-4020/Ó 2014 Published by Elsevier Ltd.

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W. Guo et al. / Tetrahedron 70 (2014) 6561e6568
Table 1
Imidazole is found in many natural products that exhibit in-
Effects of catalysts on the reaction of hydroxyacetone 9 and enone ester 10aa
teresting biological activities.8 Nevertheless, there are few reports
utilizing imidazole as functional group in catalyst design.9 In 2005,
€
Gobel’s group introduced metal-free catalysts derived from 2-
aminobenzimidazoles for the cleavage of RNA.10 Since the 2-
aminobenzimidazole group is conformationally more rigid and
bears
a
more acidic NeH bond, N-substituted 2-
Entry
Catalyst
Yieldb (%)
drc
eed (%)
aminobenzimidazoles could serve as new Brønsted acid organo-
catalysts. Several years later, this motif was introduced into chiral
1
1
2
3
4
5
6
7
8a
8b
8c
8d
8e
55
66
38
13
40
50
NR
70
79
80
85
81
4:1
4:1
3:1
ND
6:1
4:1
d
24
71
ꢁ14
ND
69
51
d
2e
3
ꢀ
cyclohexanediamine and Cinchona alkaloid by Najera’s and Park’s
group, respectively.11 Their work inspired Zheng and Zhang to de-
4
5
6
7
8
9
10
11
12
sign and apply
a novel pyrrolidine-aminobenzimidazole bi-
functional organocatalyst to asymmetric Michael reaction of
cyclohexenone with various nitroolefins.12 Very recently, our group
developed a new amphiphilic proline-derived imidazole organo-
catalysts and has shown its effectiveness in the cascade reaction of
7:1
7:1
7:1
9:1
7:1
68
72
79
81
77
a
-ketoacids with aldehydes.13 Motivated by the above success in
imidazole functionalized organocatalysts and the challenge in aldol
reaction between hydroxyacetone and other activated ketones,
a new class of imidazole derived prolineamide catalysts was pre-
pared (8aee, Fig. 1 and Scheme 2). We envisioned that these pro-
tonated compounds 8aee could activate the ketones (donor and
acceptor) simultaneously through enamine formation and double
hydrogen bonding interactions for face selectivity of substrates. On
the other hand, the N-alkyl chain on the same molecule might ef-
ficiently shield one face of pyrrolidine to get high stereoselectivity.
a
Reaction conditions: hydroxyacetone 9 (1.2 mmol), enone ester 10a (0.2 mmol),
the catalyst (0.04 mmol), propanoic acid (0.04 mmol), acetonitrile (0.5 mL), room
temperature.
b
Isolated yield of both diastereomers.
c
Determined by 1H NMR analysis of the crude reaction mixtures.
d
The ee value of anti-diastereomer was determined by chiral HPLC analysis.
No acid additive.
e
moderate yields, though no improvement was achieved for the
enantioselectivities. By contrast, catalyst 712a was found to be in-
active for the model reaction. These results highlighted the chal-
lenge in the enantioselective aldol reaction between
hydroxyacetone and activated ketone.17 To further improve the
yield and stereoselectivity, series of novel imidazole derived pro-
lineamide catalysts (8aee) were prepared (Scheme 2) and evalu-
ated. The results revealed that the reactions with these catalysts all
gave high yields in 24 h (Table 1, entries 8e12). It was found that the
length of hydrocarbon chain in catalyst has a significant effect on
the enantioselectivity. The catalyst 8d having a C16 carbon chain
exhibits the highest yield and stereoselectivity (9:1 diaster-
eoselectivity and 81% ee). These characteristics reflected the im-
portance of double hydrogen bonding activation and steric
modulation by different alkyl chain. Further optimization experi-
ments revealed that acetonitrile and propanoic acid are the best
solvent and additive for this reaction.18
Having identified the best catalyst (8d), we next focused on
varying the ester moieties of substrate 10 (Table 2). Among the
different enone esters 10, i-propyl and benzyl ester offered slightly
increased enantioselectivity (Table 2, entries 3 and 5, entries 6 and
7). For synthetic convenience, iso-propyl ester was chosen for fur-
ther optimization. In general, the reaction temperature and sub-
strate concentration have slight effects on enantioselectivity (Table
2, entries 6 and 7, entries 8e10). Through these screenings, the
optimized reaction conditions were found to be a combination of
20 mol % of 8d with 20 mol % of propanoic acid in acetonitrile
(0.5 mL) at 0 ꢀC.
Fig. 1. Organocatalysts employed in this study.
Scheme 2. Preparation of the imidazole-based prolineamide catalysts 8ae8e.
2. Results and discussion
2.2. Generality
2.1. Optimization of the reaction conditions
To validate our hypothesis, reaction of hydroxyacetone 9 and
Under the optimal conditions, hydroxyacetone 9 and various
g-
aryl or alkyl-substituted -unsaturated -keto esters 10 were
b
,g
a
unsaturated
a
-ketoester 10a14 was selected as model reaction for
examined to investigate the reaction scope, and the results were
summarized in Table 3. For the acceptors containing aromatic rings,
the position and electronic property of substituent have little effect
on the enantioselectivity, and aldol products were obtained with
good to excellent enantioselectivities and diastereoselectivities (up
to 92% yield, 90% ee and 15:1 dr, Table 3, entries 1e10). Acceptors
containing heterocyclic rings, such as thiophene, also worked well
the screening of catalysts. With known proline-derivated organo-
catalysts 1e4, catalyst 2 showed higher catalytic activity and
enantioselectivity than others, with which 11a was obtained in
moderate yield and stereoselectivity (Table 1, entry 2). Then several
prolineamide type organocatalysts were tested (Talbe 1, entries
5e7). Singh’s catalyst 515 and Gong’s catalyst 616 gave products in

W. Guo et al. / Tetrahedron 70 (2014) 6561e6568
6563
Table 2
Optimizing the reaction conditionsa
Scheme 3. Further investigation on the substrate scope.
Entry
R
Yieldb (%)
t (h)
drc (%)
eed (%)
1
2
3
4
Me
Et
i-Pr
t-Bu
Bn
i-Pr
Bn
i-Pr
i-Pr
i-Pr
75
82
83
85
70
50
57
60
70
80
24
24
24
24
24
44
44
50
50
50
9:1
10:1
12:1
16:1
12:1
12:1
13:1
13:1
10:1
12:1
81
82
83
81
83
86
86
87
85
85
enhances the pharmacological activities.19 However, the enamine-
based organocatalytic synthesis of tertiary alcohols bearing tri-
fluoromethyl groups is still an elusive challenge up to date.20
Keeping this fact in mind, a slight modification of the conditions
5
6e
7e
8e,f
9e,g
10e,h
used for b,g-unsaturated a-keto esters led to an efficient method
for the conversion of trifluoromethyl ketone. The trifluoromethyl
group functionalized tertiary alcohol was obtained in good yield
and stereoselectivity.
a
Reaction conditions: 9 (6 equiv), 10 (0.2 mmol), 1e (0.04 mmol), propanoic acid
(0.04 mmol), acetonitrile (0.5 mL), room temperature.
b
Isolated yield of both diastereomers.
2.3. Synthetic utilization
c
Determined by 1H NMR analysis of the crude product.
d
Determined by HPLC analysis on a chiral stationary phase.
e
ꢀC.
Gram-scale synthesis of the anti-1,2-diol 11s was performed to
evaluate the synthetic potential of the catalytic system, exposure of
3.5 mmol of 10s to the optimized conditions, the corresponding 11s
was obtained in 80% yield (1.0 g) with 86% ee.
Furthermore, compound 12s and 13s could be obtained after a sim-
ple reduction of 11s with different reaction conditions (Scheme 4).
0
f
Hydroxyacetone (3 equiv), 0.5 mL acetonitrile.
Hydroxyacetone (3 equiv), 0.25 mL acetonitrile.
Hydroxyacetone (6 equiv), 0.25 mL CH3CN.
g
h
Table 3
Aldol reaction of 9 with various enone ester 10a
Entry
R
Yieldb (%)
drc (%)
eed (%)
1
2
3
4
5
6
7
8
Ph
11c (80)
11f (90)
11g (80)
11h (85)
11i (82)
11j (87)
11k (92)
11l (80)
11m (73)
11n (85)
11o (79)
11p (65)
11q (57)
11r (58)
13:1
10:1
15:1
10:1
10:1
15:1
11:1
11:1
15:1
14:1
12:1
8:1
87
86
87
85
90
88
86
87
87
86
84
75
64
66
2-ClC6H4
4-ClC6H4
3-ClC6H4
4-BrC6H4
4-FC6H4
3-BrC6H4
4-CF3C6H4
4-CH3C6H4
3-CH3C6H4
2-Thienyl
n-Hexyle
cyclohexyle
iso-propyle
Scheme 4. Gram-scale asymmetric synthesis of 11s and synthetic application.
9
10
11
12
13
14
2.4. Absolute configuration
9:1
10:1
The absolute configuration of product was assigned by X-ray
structural analysis of adduct 11s to be (2R,3R).
a
Reaction conditions: 9 (1.2 mmol), 10 (0.2 mmol), 1e (0.04 mmol), propanoic
acid (0.04 mmol), CH3CN (0.5 mL), 0 ꢀC. TLC monitored.
b
Isolated yield of both diastereomers.
2.5. Transition state
c
Determined by 1H NMR analysis of the crude product.
d
The ee value of the major diastereomer was determined by chiral HPLC analysis.
Methyl ester, at room temperature.
On the basis of experimental results described above, a stereo-
chemical model was proposed to account for the high enantiose-
lectivity of the present reaction. As shown in Scheme 5, catalyst 8d
was proposed as a bifunctional catalyst. The pyrrolidine moiety of
catalyst reacts with hydroxyacetone to form an enamine and the
e
for the aldol reaction, affording the desired adduct in good yield,
high diastereoselectivity, and enantioselectivity (Table 3, entry 11).
It’s worthy to note that the two diastereomers of the above aldol
adducts can be separated by careful column chromatography. No-
ticeably, the elusive alkyl-substituted b,g-unsaturated a-keto esters
are also compatible to our catalytic system, and the desired prod-
ucts with good diasteresoselectivities and moderate enantiose-
lectivities were obtained. To our best knowledge, this is the first
example for these inert substrates as acceptors in aldol reactions.14c
To further demonstrate the utility of these imidazole-based
prolineamide catalysts, we evaluated trifluoromethyl ketone as
reactive ketone electrophile (Scheme 3). It has been reported that
the presence of fluorine atoms in pharmaceutical compounds often
Scheme 5. A possible stereochemical model.

6564
W. Guo et al. / Tetrahedron 70 (2014) 6561e6568
protonated 2-aminoimidazole derivated amide activates the enone
ester via double hydrogen bonds interactions. Since the carbonyl
group of enone ester was assembled closely to the in situ generated
enamine, excellent chemselectivity of aldol adduct was obtained.
The enamine attacked the enone ester from the Re-face to afford
the product, which was consistent with the experimental results.
(1.5 equiv, 7.2 g) were added to a solution of I (3 g, 21.71 mmol) in
dry DMF (50 mL) at 40 ꢀC, the mixture was stirred for 24 h. Water
was added to the reaction mixture, and the product was extracted
with DCM. The extract was washed with water for several times
then dried over anhydrous NaSO4. The solvent was evaporated
under reduced pressure. The resulting residue was purified by
column chromatography on silica gel (eluent: petroleum ether/
acetone, 2:1,1% TEA) to give the desired product as brown oil. Yield:
3. Conclusion
91%. 1H NMR (400 MHz, CDCl3)
d
8.37 (s, 1H), 6.69 (d, J¼1.5 Hz, 1H),
In summary, we have synthesized a novel imidazole-based pro-
lineamide organocatalyst, which is a potent catalyst for the asym-
metric Aldol reaction of ketones with hydroxyacetone. The adducts
anti-1,2-diols bearing a functionalized chiral tertiary alcohol moiety
were obtained in high yield (up to 92%) and stereoselectivity (up to
15:1 dr and 90% ee). Furthermore, trifluoromethyl ketones are also
demonstrated to be a viable substrate of the aldol reaction with
6.62 (d, J¼1.5 Hz, 1H), 3.84 (t, J¼7.2 Hz, 2H), 2.99 (d, J¼8.0 Hz, 6H),
1.75e1.53 (m, 2H), 1.34e1.13 (m, 14H), 0.84 (t, J¼6.9 Hz, 3H); 13C
NMR (101 MHz, CDCl3) d 154.83,152.09,124.59,115.81, 44.03, 40.34,
34.21, 31.96, 30.53, 29.63, 29.59, 29.38, 29.21, 26.62, 22.74, 14.18;
HRMS (ESI) m/z calcd for C16H30N4 [MþH]þ: 279.2549, found:
279.2542.
hydroxyacetone. Further investigations toward
a
deeper un-
4.2.3. (E)-N0-(1-Dodecyl-1H-imidazol-2-yl)-N,N-dimethylformimida-
derstanding of the reaction mechanism and extension of the current
method to other reactions are being pursued in this laboratory.
mide (II-12). Yield 95%, brown oil. 1H NMR (400 MHz, CDCl3)
d 8.44
(s, 1H), 6.72 (d, J¼1.5 Hz,1H), 6.64 (d, J¼1.5 Hz,1H), 3.86 (t, J¼7.2 Hz,
2H), 3.02 (d, J¼11.5 Hz, 6H), 1.69 (m, 2H), 1.34e1.18 (m, 18H), 0.87 (t,
4. Experimental
J¼6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 154.83, 152.09, 124.59,
115.81, 44.03, 40.34, 34.21, 31.96, 30.53, 29.63, 29.59, 29.38, 29.21,
26.62, 22.74, 14.18; HRMS (ESI) m/z calcd for C18H34N4 [MþH]þ:
307.2862, found: 307.2848.
4.1. General methods
Unless otherwise noted, solvents were treated prior to use
according to the standard methods. All chemicals were obtained
from commercial sources and were used without further purifica-
tion. Column chromatography was carried out on silica gel
(300e400 mesh) using a forced flow of eluent at 0.3e0.5 bar pres-
sure. For TLC, silica gel GF254 was used and visualized by fluorescence
quenching under UV light. NMR spectra were recorded on a Bruker
400 MHz or 500 MHz NMR spectrometer in the solvents indicated.
The chemical shifts for 1H NMR were recorded in parts per million
(ppm) downfield from tetramethylsilane (TMS) with CDCl3
(7.26 ppm) as the internal standard. The chemical shifts for 13C NMR
were recorded in parts per million (ppm) downfield using the central
peak of CDCl3 (77.16 ppm) as the internal standard. Coupling con-
stants (J) are reported in hertz (Hz) and refer to apparent peak
multiplications. High performance liquid chromatography (HPLC)
was performed on Agilent HPLC 1100 or 1200 equipped with Daicel
chiral AD-H or OD-H column. High-resolution mass spectra for all
the new compounds were done by an LTQ-Orbitrap instrument (ESI)
(Thermo Fisher Scientific, USA). Optical rotations were measured at
25 ꢀC in CHCl3 on a Jasco Digital Polarimeter.
4.2.4. (E)-N,N-Dimethyl-N0-(1-tetradecyl-1H-imidazol-2-yl)for-
mimidamide (II-14). Yield 89%, brown oil. 1H NMR (400 MHz,
CDCl3)
3.00 (d, J¼7.8 Hz, 6H), 1.68 (m, 2H), 1.24 (m, 22H), 0.85 (t, J¼6.7 Hz,
3H); 13C NMR (101 MHz, CDCl3)
154.84, 152.09, 124.59, 115.82,
d
8.38 (s, 1H), 6.70 (s, 1H), 6.62 (s, 1H), 3.85 (t, J¼7.2 Hz, 2H),
d
44.05, 40.34, 34.22, 31.99, 30.54, 29.76, 29.75, 29.73, 29.69, 29.60,
29.43, 29.22, 26.64, 22.76, 14.20; HRMS (ESI) m/z calcd for C20H38N4
[MþH]þ: 335.3175, found: 335.3161.
4.2.5. (E)-N0-(1-Hexadecyl-1H-imidazol-2-yl)-N,N-dimethylformimi-
damide (II-16). Yield 80%, brown oil. 1H NMR (400 MHz, CDCl3)
d
8.42 (s, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 3.86 (t, J¼7.2 Hz, 2H), 3.02 (d,
J¼12.5 Hz, 6H), 1.69 (m, 2H), 1.26 (m, 26H), 0.87 (t, J¼6.6 Hz, 3H);
13C NMR (101 MHz, CDCl3)
155.53, 152.62, 125.01, 116.39, 44.66,
d
40.94, 34.81, 32.58, 31.10, 30.35, 30.33, 30.31, 30.27, 30.18, 30.01,
29.80, 27.22, 23.34, 14.77; HRMS (ESI) m/z calcd for C22H42N4
[MþH]þ: 363.3488, found: 363.3454.
4.2.6. (E)-N,N-Dimethyl-N0-(1-octadecyl-1H-imidazol-2-yl)for-
mimidamide (II-18). Yield 71%, brown waxy solid. 1H NMR
4.2. Procedure of preparation of catalysts 8a, 8b, 8c, 8d, and
8e
(400 MHz, CDCl3) d 8.40 (s, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 3.86 (t,
J¼7.2 Hz, 2H), 3.01 (d, J¼6.9 Hz, 6H), 1.69 (m, 2H), 1.38e1.15 (m,
30H), 0.87 (t, J¼6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 154.87,
4.2.1. 2-(Dimethylaminomethylene)aminoimidazole
a
(I). This
is
152.10, 124.59, 115.84, 44.06, 40.38, 34.23, 32.02, 30.56, 29.80,
29.76, 29.71, 29.63, 29.46, 29.25, 26.66, 22.79, 14.23; HRMS (ESI) m/
z calcd for C24H46N4 [MþH]þ: 391.3801, found: 391.3788.
known compound.21aec 2-Aminoimidazole sulfate (13.3 g,
49.3 mmol) was dissolved in water (200 mL), sodium carbonate
(16 g, 150 mmol) was added, and the mixture was stirred at rt for
40 min. Water was removed in vacuo. The residue was slurried with
anhydrous ethanol and filtered through Celite, and the solvent was
removed in vacuo to give 2-aminoimidazole as orange oil. The
residue was dissolved in N,N-dimethylformamide dimethyl acetal
(50 mL), and the suspension was stirred at rt overnight. After
evaporation of solvent, the product was purified by column chro-
matography (DCM/TEA, 3:1) to give intermediate I as a white solid
4.2.7. 1-(n-Alkyl)-1H-imidazol-2-amine (III). Intermediate II was
dissolved in 6 N hydrochloric acid (50 mL), and the solution was
heated under reflux for 5 h. The solvent was evaporated under
reduced pressure, and the resulting residue was dissolved in DCM
and K2CO3 was added. The mixture was stirred at room tempera-
ture for 1 h, and then filtered. The filtrate was concentrated under
reduced pressure to give the desired product III as reddish waxy
solid, which was used without further purification.
(11.2 g, yield: 81%). 1H NMR (400 MHz, CDCl3)
d 10.51 (br, 1H), 8.52
(s, 1H), 6.75 (s, 1H), 3.05 (d, J¼20.0 Hz, 1H); 13C NMR (101 MHz,
CDCl3)
d
155.99, 152.83, 119.32(br), 40.74, 34.75; HRMS (ESI) m/z
4.2.8. (S)-Benzyl 2-((1-decyl-1H-imidazol-2-yl)carbamoyl)pyrroli-
calcd for C6H10N4 [MþH]þ: 139.0984, found: 139.0973.
dine-1-carboxylate (IV-10).20d To a dry DCM (10 mL) solution of N-
Cbz-L-proline (2.2 g, 8.75 mmol) was slowly added a DCM (20 mL)
4.2.2. (E)-N0-(1-Decyl-1H-imidazol-2-yl)-N,N-dimethylformimida-
mide (II-10). Potassium tert-butoxide (2 equiv, 4.87 g) and C10H21Br
solution of DCC (1.81 g, 8.75 mmol) at 0 ꢀC under a nitrogen at-
mosphere. After stirring for 30 min, a DCM (40 mL) solution of

W. Guo et al. / Tetrahedron 70 (2014) 6561e6568
6565
intermediate III-10 (8.75 mmol) was slowly added to the mixture at
0 ꢀC and the mixture was slowly warmed to room temperature and
further stirred overnight. After removal of the precipitate by fil-
tration, the filtrate was concentrated under reduced pressure. The
crude product was purified by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate, 3:1, 1% TEA then ethyl ac-
etate, 1% TEA) to give the desired product as brown oil. Yield 55%.
The NMR spectrum is complicated by the presence of Cbz rotamers. 1H
29.56, 29.45, 29.24, 26.77, 26.64, 26.55, 24.41, 23.48, 22.78, 14.21;
25
[a
]
ꢁ59.51 (c 1.03, CHCl3); HRMS (ESI) m/z calcd for C34H54N4O3
D
[MþH]þ: 567.4274, found: 567.4260.
4.2.13. (S)-N-(1-Decyl-1H-imidazol-2-yl)pyrrolidine-2-carboxamide
(8a). To a solution of intermediate IV-10 in anhydrous MeOH
(30 mL) was added Pd/C (10%) at room temperature handled in the
glove box. The reaction mixture was stirred under H2 atmosphere
(5 atm) for 3 h. After Pd/C was removed by filtration, the filtrate was
concentrated under reduced pressure. The crude product can be
purified by column chromatography on silica gel (eluent: ethyl
acetate, then DCM/MeOH¼10/1, containing 1% TEA) to get the de-
sired product as light yellow oil. Yield 71%. 1H NMR (400 MHz,
NMR (400 MHz, CDCl3)
d 7.50e7.19 (m, 5H), 6.80e6.35 (m, 2H),
5.21e5.02 (m, 2H), 4.66e4.27 (m, 1H), 3.95e3.34 (m, 4H),
2.32e1.75 (m, 4H), 1.62 (m, 2H), 1.36e1.13 (m, 14H), 0.87 (t,
J¼6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 155.43, 155.20, 137.39,
137.14, 128.48, 128.08, 127.90, 127.48, 127.34, 114.33, 66.84, 66.34,
65.94, 62.83, 47.33, 46.94, 45.20, 44.88, 31.95, 31.88, 29.69, 29.60,
CDCl3)
d
6.87 (d, J¼1.5 Hz, 1H), 6.71 (d, J¼1.5 Hz, 1H), 6.65e5.99 (br,
29.45, 29.37, 29.23, 26.64, 26.55, 24.41, 23.48, 22.75, 15.37, 14.20;
2H), 3.98 (dd, J¼9.0, 5.1 Hz, 1H), 3.83 (t, J¼7.3 Hz, 2H), 3.17e3.05 (m,
2H), 2.28e2.04 (m, 2H), 1.84e1.70 (m, 4H), 1.28e1.26 (m, 14H), 0.88
25
[
a]
ꢁ79.99 (c 1.00, CHCl3); HRMS (ESI) m/z calcd for C26H38N4O3
D
[MþH]þ: 455.3022, found: 455.3024.
(t, J¼6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 176.87, 141.21, 122.54,
117.32, 61.31, 47.28, 45.83, 31.90, 31.07, 30.06, 29.54, 29.50, 29.31,
4.2.9. (S)-Benzyl 2-((1-dodecyl-1H-imidazol-2-yl)carbamoyl)pyrro-
lidine-1-carboxylate (IV-12). The NMR spectrum is complicated by
the presence of Cbz rotamers. Yield 74%, brown oil. 1H NMR
29.16, 26.66, 26.10, 22.70, 14.15; [
a
]
D
25 ꢁ51.51 (c 0.59, CHCl3); HRMS
(ESI) m/z calcd for C18H32N4O [MþH]þ: 321.2654, found: 321.2643.
(400 MHz, CDCl3)
d
7.39e7.15 (m, 5H), 6.68e6.50 (m, 2H),
4.2.14. (S)-N-(1-Dodecyl-1H-imidazol-2-yl)pyrrolidine-2-
5.22e5.03 (m, 2H), 4.49e4.40 (m, 1H), 3.82e3.46 (m, 4H),
2.28e1.81 (m, 4H), 1.71e1.58 (m, 2H), 1.27e1.19 (m, 18H), 0.87 (t,
carboxamide (8b). Yield 60%, light yellow oil. 1H NMR (400 MHz,
CDCl3)
d
6.82 (d, J¼1.6 Hz, 1H), 6.70 (d, J¼1.6 Hz, 1H), 3.87 (dd, J¼9.1,
J¼6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d
155.45, 155.20, 137.41,
5.2 Hz, 1H), 3.77 (t, J¼7.3 Hz, 2H), 3.07e2.97 (m, 2H), 2.22e1.96 (m,
137.15, 128.48, 128.07, 127.91, 127.48, 127.34, 114.29, 66.84, 66.34,
65.94, 62.86, 47.33, 46.94, 45.19, 44.87, 31.99, 31.88, 29.72, 29.70,
2H), 1.78e1.66 (m, 4H), 1.23e1.21 (m, 18H), 0.84 (t, J¼6.8 Hz, 3H);
13C NMR (101 MHz, CDCl3)
d 176.82, 141.29, 122.49, 117.30, 61.32,
29.65, 29.58, 29.56, 29.43, 29.24, 26.64, 26.55, 24.41, 23.48, 22.77,
47.28, 45.84, 31.95, 31.07, 30.07, 29.66, 29.60, 29.52, 29.38, 29.18,
25
25
14.21; [
a
]
D
ꢁ73.57 (c 1.23, CHCl3); HRMS (ESI) m/z calcd for
26.68, 26.09, 22.73, 14.17; [
a]
ꢁ41.34 (c 0.61, CHCl3); HRMS (ESI)
C
28H42N4O3 [MþH]þ: 483.3335, found: 483.3318.
m/z calcd for C20H36N4O [MþDH]þ: 349.2967, found: 349.2965.
4.2.10. (S)-Benzyl 2-((1-tetradecyl-1H-imidazol-2-yl)carbamoyl)pyr-
rolidine-1-carboxylate (IV-14). Yield 44%, brown waxy solid. The
NMR spectrum is complicated by the presence of Cbz rotamers. 1H
4.2.15. (S)-N-(1-Tetradecyl-1H-imidazol-2-yl)pyrrolidine-2-
carboxamide (8c). Yield 75%, light yellow oil. 1H NMR (400 MHz,
CDCl3)
d
6.86 (s, 1H), 6.74 (s, 1H), 3.89 (dd, J¼9.1, 5.2 Hz, 1H), 3.81 (t,
NMR (400 MHz, CDCl3)
d
7.39e7.15 (m, 5H), 6.68e6.50 (m, 2H),
J¼7.3 Hz, 2H), 3.10e3.01 (m, 2H), 2.26e1.98 (m, 2H), 1.82e1.70 (m,
5.22e5.03 (m, 2H), 4.49e4.40 (m, 1H), 3.82e3.45 (m, 4H),
2.28e1.81 (m, 4H), 1.69e1.59 (m, 2H), 1.24e1.19 (m, 22H), 0.87 (t,
4H), 1.27e1.24 (m, 22H), 0.87 (t, J¼6.7 Hz, 3H); 13C NMR (101 MHz,
CDCl3)
d 176.95, 141.04, 122.81, 117.43, 61.30, 47.35, 45.88, 31.98,
J¼6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d
155.45, 155.20, 137.39,
31.11, 30.10, 29.74, 29.71, 29.69, 29.62, 29.53, 29.42, 29.20, 26.69,
25
137.13, 128.48, 128.08, 127.90, 127.48, 127.34, 114.28, 66.84, 66.34,
62.85, 47.33, 46.94, 45.19, 44.88, 32.01, 31.88, 29.78, 29.73, 29.66,
26.18, 22.75, 14.19; [
a
]
ꢁ37.08 (c 0.48, CHCl3); HRMS (ESI) m/z
D
calcd for C22H40N4O [MþH]þ: 377.3280, found: 377.3269.
29.58, 29.56, 29.44, 29.24, 26.65, 26.55, 24.41, 23.48, 22.78, 14.21;
25
[
a]
ꢁ71.00 (c 1.00, CHCl3); HRMS (ESI) m/z calcd for C30H46N4O3
4.2.16. (S)-N-(1-Hexadecyl-1H-imidazol-2-yl)pyrrolidine-2-
D
[MþH]þ: 511.3648, found: 511.3641.
carboxamide (8d). White waxy solid. 1H NMR (400 MHz, CDCl3)
d
6.86 (s, 1H), 6.74 (s, 1H), 3.91 (dd, J¼9.0, 5.2 Hz, 1H), 3.81 (t,
4.2.11. (S)-Benzyl 2-((1-hexadecyl-1H-imidazol-2-yl)carbamoyl)pyr-
rolidine-1-carboxylate (IV-16). Yield 50%, brown waxy solid. The
NMR spectrum is complicated by the presence of Cbz rotamers. 1H
J¼7.3 Hz, 2H), 3.11e3.03 (m, 2H), 2.27e1.99 (m, 2H), 1.83e1.70 (m,
4H), 1.27e1.24 (m, 26H), 0.87 (t, J¼6.7 Hz, 3H); 13C NMR (101 MHz,
CDCl3)
d 176.97, 140.96, 123.00, 117.46, 61.32, 47.37, 45.89, 31.98,
NMR (400 MHz, CDCl3)
d
7.39e7.15 (m, 5H), 6.68e6.50 (m, 2H),
31.10, 30.10, 29.75, 29.72, 29.68, 29.61, 29.53, 29.42, 29.19, 26.70,
25
5.22e5.03 (m, 2H), 4.49e4.40 (m, 1H), 3.82e3.45 (m, 4H),
2.29e1.82 (m, 4H), 1.71e1.59 (m, 2H), 1.25e1.19 (m, 26H), 0.88 (t,
26.20, 22.74, 14.17; [
a
]
ꢁ35.75 (c 0.69, CHCl3); HRMS (ESI) m/z
D
calcd for C24H44N4O [MþH]þ: 405.3593, found: 405.3582.
J¼6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 155.47, 155.21, 137.42,
137.16, 128.48, 128.07, 127.91, 127.50, 127.33, 114.22, 66.85, 66.33,
62.92, 47.31, 46.93, 45.13, 44.85, 32.01, 31.88, 29.79, 29.76, 29.75,
4.2.17. (S)-N-(1-Octadecyl-1H-imidazol-2-yl)pyrrolidine-2-
carboxamide (8e). Yield 60%, white waxy solid. 1H NMR (400 MHz,
29.67, 29.57, 29.45, 29.24, 26.64, 26.55, 24.41, 23.48, 22.78, 14.21;
CDCl3)
d
6.85 (s, 1H), 6.72 (s, 1H), 3.91 (dd, J¼9.0, 5.2 Hz, 1H), 3.81 (t,
25
[
a]
ꢁ64.29 (c 1.07, CHCl3); HRMS (ESI) m/z calcd for C32H50N4O3
J¼7.3 Hz, 2H), 3.12e3.01 (m, 2H), 2.26e1.98 (m, 2H), 1.82e1.69 (m,
D
[MþH]þ: 539.3961, found: 539.3940.
4H), 1.27e1.24 (m, 30H), 0.87 (t, J¼6.5 Hz, 3H); 13C NMR (101 MHz,
CDCl3)
d 177.04, 140.78, 123.13, 117.53, 61.29, 47.40, 45.90, 31.99,
4.2.12. (S)-Benzyl 2-((1-octadecyl-1H-imidazol-2-yl)carbamoyl)pyr-
rolidine-1-carboxylate (IV-18). Yield 59%, brown waxy solid. The
NMR spectrum is complicated by the presence of Cbz rotamers. 1H
31.13, 30.12, 29.76, 29.72, 29.69, 29.62, 29.54, 29.43, 29.20, 26.70,
25
26.25, 22.75, 14.19; [
a
]
ꢁ34.69 (c 0.64, CHCl3); HRMS (ESI) m/z
D
calcd for C26H48N4O [MþH]þ: 433.3906, found: 433.3899.
4.3. Typical procedure for the cross aldol reactions
To a mixture of catalyst 8d (0.04 mmol) and propanoic acid (3 ml,
NMR (400 MHz, CDCl3)
d 7.39e7.15 (m, 5H), 6.65e6.50 (m, 2H),
5.22e5.03 (m, 2H), 4.48e4.40 (m, 1H), 3.82e3.45 (m, 4H),
2.29e1.81 (m, 4H), 1.69e1.59 (m, 2H), 1.30e1.19 (m, 30H), 0.88 (t,
J¼6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d
155.17, 137.42, 128.48,
128.07, 127.92, 127.50, 127.33, 124.09, 115.33, 66.86, 66.33, 62.91,
47.31, 46.93, 45.05, 44.84, 32.01, 31.88, 29.79, 29.76, 29.75, 29.67,
0.04 mmol) in CH3CN (0.5 mL), unmodified hydroxyacetone
(6 equiv, 1.2 mmol) was added. After the mixture was stirred at 0 ꢀC

6566
W. Guo et al. / Tetrahedron 70 (2014) 6561e6568
for 15 min, the corresponding enone ester (0.2 mmol) was added.
After completion of the reaction (monitored by TLC), a small part of
the mixture was directly purified by preparative thin layer chro-
matography (petroleum ether/ethyl acetate 2:1) to give the desired
product and then the enantioselectivity was measured by chiral
HPLC. The last part of the reaction mixture was carefully purified by
column chromatography on silica gel (petroleum ether/ethyl ace-
tate 5:1) to give the desired product as separated diastereomer.
tR¼19.14 min (major), tR¼21.24 min (minor); [
CHCl3)]; 1H NMR (400 MHz, CDCl3)
a
]
25 ꢁ130.34 (c 0.86,
D
d
7.47 (d, J¼7.9 Hz, 2H), 7.29 (d,
J¼7.9 Hz, 2H), 6.92 (d, J¼15.8 Hz, 1H), 6.50 (d, J¼15.8 Hz, 1H),
5.17e5.11 (m, 1H), 4.57 (d, J¼6.6 Hz, 1H), 3.98 (d, J¼6.7 Hz, 1H), 3.86
(s, 1H), 2.19 (s, 3H), 1.33 (dd, J¼15.4, 6.0 Hz, 6H); 13C NMR (101 MHz,
CDCl3)
d 205.80, 172.07, 135.41, 132.58, 131.63, 129.00, 126.85,
122.93, 81.45, 80.25, 72.22, 29.31, 22.43, 22.26; HRMS (ESI) m/z
calcd for C16H19BrO5 [MþNa]þ: 393.0314, found: 395.0283.
4.3.1. (2R,3R)-Isopropyl
2,3-dihydroxy-4-oxo-2-((E)-styryl)penta-
4.3.6. (2R,3R)-Isopropyl 2-((E)-4-fluorostyryl)-2,3-dihydroxy-4-
oxopentanoate (11j). Yield 38.8 mg, 87%; white solid, 93e95 ꢀC;
88% ee, 15:1 dr [determined by HPLC analysis: chiral OD-H, hexane/
noate (11c). Yield 32.8 mg; white solid, mp 98e100 ꢀC; 80% yield,
87% ee, 13:1 dr [determined by HPLC analysis: chiral AD-H, hexane/
isopropanol¼95:5, 0.8 mL/min, 254 nm UV detector; tR¼31.87 min
isopropanol¼95:5, 0.8 mL/min, 254 nm UV detector; tR¼16.8 min
25
25
(minor), tR¼36.51 min (major); [
a]
ꢁ164.8 (c 0.52, CHCl3)]; 1H
(major), tR¼18.6 min (minor); [
a
]
ꢁ176.27 (c 0.70, CHCl3)]; 1H
D
D
NMR (400 MHz, CDCl3)
d
7.45e7.28 (m, 5H), 6.99 (d, J¼15.8 Hz, 1H),
NMR (400 MHz, CDCl3)
d
7.40 (dd, J¼8.5, 5.5 Hz, 2H), 7.04 (t,
6.50 (d, J¼15.8 Hz, 1H), 5.20e5.10 (m, 1H), 4.60 (d, J¼6.6 Hz, 1H),
J¼8.6 Hz, 2H), 6.94 (d, J¼15.8 Hz, 1H), 6.41 (d, J¼15.8 Hz, 1H),
5.19e5.10 (m, 1H), 4.57 (d, J¼6.9 Hz, 1H), 3.97 (d, J¼6.9 Hz, 1H), 3.83
(s,1H), 2.20 (s, 3H),1.33 (dd, J¼14.9, 6.3 Hz, 6H); 13C NMR (101 MHz,
4.00 (d, J¼6.8 Hz, 1H), 3.86 (s, 1H), 2.21 (s, 3H), 1.34 (dd, J¼16.3,
6.2 Hz, 6H); 13C NMR (101 MHz, CDCl3)
d 205.91, 172.28, 136.52,
132.78, 129.44, 129.02, 127.52, 126.08, 81.53, 80.34, 72.09, 29.41,
CDCl3)
d
205.87,171.66,162.83 (d, J¼249.07 Hz),132.15 (d, J¼3.3 Hz),
22.43, 22.28; HRMS (ESI) m/z calcd for
315.1208, found: 315.1172.
C
16H20O5 [MþNa]þ:
131.00, 128.52 (d, J¼8.18 Hz), 125.28 (d, J¼2.02 Hz), 115.81 (d,
J¼21.72 Hz), 80.94, 79.66, 71.54, 28.74, 21.83, 21.67; HRMS (ESI) m/z
calcd for C16H19FO5 [MþNa]þ: 333.1114, found: 333.1107.
4.3.2. (2R,3R)-Isopropyl 2-((E)-2-chlorostyryl)-2,3-dihydroxy-4-
oxopentanoate (11f). Yield 43.1 mg, light yellow solid, mp
83e86 ꢀC; 90% yield, 86% ee, 10:1 dr [determined by HPLC analysis:
chiral AD-H, hexane/isopropanol¼97:3, 0.8 mL/min, 254 nm UV
4.3.7. (2R,3R)-Isopropyl 2-((E)-3-bromostyryl)-2,3-dihydroxy-4-
oxopentanoate (11k). Yield 52.3 mg, 92%; white solid, mp
81e84 ꢀC; 86% ee, 11:1 dr [determined by HPLC analysis: chiral OD-
H, hexane/isopropanol¼95/5, 0.8 mL/min, 254 nm UV detector;
detector; tR¼51.06 min (minor), tR¼67.48 min (major); [
a
]
25 ꢁ150.4
D
(c 0.6, CHCl3)]; 1H NMR (400 MHz, CDCl3)
d
7.52 (dd, J¼7.3, 1.9 Hz,
tR¼17.64 min (minor), tR¼19.13 min (major); [
a
]
25 ꢁ149.86 (c 0.80,
D
1H), 7.40e7.34 (m, 2H), 7.28e7.23 (m, 2H), 6.49 (d, J¼15.8 Hz, 1H),
5.21e5.12 (m, 1H), 4.58 (d, J¼6.9 Hz, 1H), 3.99 (d, J¼6.9 Hz, 1H), 3.86
(s, 1H), 2.23 (s, 3H), 1.35 (dd, J¼11.8, 6.3 Hz, 6H); 13C NMR (101 MHz,
CHCl3)]; 1H NMR (400 MHz, CDCl3)
d
7.58 (s, 1H), 7.41 (d, J¼7.9 Hz,
1H), 7.33 (d, J¼7.9 Hz, 1H), 7.24e7.20 (m, 1H), 6.92 (d, J¼15.8 Hz,
1H), 6.51 (d, J¼15.8 Hz, 1H), 5.15 (m, 1H), 4.58 (d, J¼6.9 Hz, 1H), 3.99
(d, J¼6.9 Hz, 1H), 3.88 (s, 1H), 2.19 (s, 3H), 1.34 (dd, J¼13.4, 6.3 Hz,
CDCl3)
d 205.80, 172.04, 134.93, 134.30, 130.60, 129.96, 129.51,
129.43, 127.88, 127.63, 81.56, 80.44, 72.20, 29.41, 22.43, 22.27;
HRMS (ESI) m/z calcd for C16H19ClO5 [MþNa]þ: 349.0819, found:
349.0812.
6H); 13C NMR (101 MHz, CDCl3)
d 205.77, 172.05, 138.62, 131.88,
131.43, 130.98, 130.11, 127.64, 126.41, 123.61, 81.48, 80.25, 72.31,
29.36, 22.45, 22.27. HRMS (ESI) m/z calcd for C16H19BrO5 [MþNa]þ:
393.0314, found: 395.0297.
4.3.3. (2R,3R)-Isopropyl 2-((E)-4-chlorostyryl)-2,3-dihydroxy-4-
oxopentanoate (11g). Yield 38.3 mg, 80%; white solid, mp
96e99 ꢀC; 87% ee, 15:1 dr [determined by HPLC ananlysis: chiral
AD-H, hexane/isopropanol¼95:5, 0.8 mL/min, 254 nm UV detector;
4.3.8. (2R,3R)-Isopropyl
2,3-dihydroxy-4-oxo-2-((E)-4-(trifluorom
ethyl)styryl)pentanoate (11l). Yield 43.7 mg, 80%; white solid, mp
90e92 ꢀC; 87% ee, 11:1 dr [determined by HPLC analysis: chiral OD-
tR¼46.91 min (major), tR¼51.34 min (minor); [
a]
25 ꢁ200.70 (c 0.42,
H, hexane/isopropanol¼95:5, 0.8 mL/min, 254 nm UV detector;
D
25
CHCl3)]; 1H NMR (400 MHz, CDCl3)
d
7.37e7.31 (m, 4H), 6.94 (d,
tR¼15.23 (major), tR¼16.84 min (minor); [
a]
D
ꢁ151.45 (c 0.48,
J¼15.8 Hz, 1H), 6.48 (d, J¼15.8 Hz, 1H), 5.18e5.12 (m, 1H), 4.57 (d,
CHCl3)]; 1H NMR (400 MHz, CDCl3)
d
7.61 (d, J¼8.3 Hz, 2H), 7.53 (d,
J¼6.8 Hz, 1H), 3.96 (d, J¼6.9 Hz, 1H), 3.84 (s, 1H), 2.19 (s, 3H), 1.33
J¼8.2 Hz, 2H), 7.02 (d, J¼15.8 Hz, 1H), 6.61 (d, J¼15.8 Hz, 1H), 5.16 (m,
1H), 4.59 (d, J¼6.9 Hz, 1H), 3.98 (d, J¼7.0 Hz, 1H), 3.89 (s, 1H), 2.20 (s,
(dd, J¼15.3, 6.2 Hz, 6H); 13C NMR (101 MHz, CDCl3)
d 205.79, 171.82,
134.97, 134.77, 131.58, 129.62, 128.70, 126.72, 81.47, 80.22, 72.22,
29.31, 22.42, 22.26; HRMS (ESI) m/z calcd for C16H19ClO5 [MþNa]þ:
349.0819, found: 349.0812.
3H), 1.34 (dd, J¼16.1, 6.3 Hz, 6H); 13C NMR (101 MHz, CDCl3)
d 205.70,
171.95, 139.93, 131.46, 128.83, 127.69, 126.40 (q, J¼3.6 Hz), 124.7 (q,
J¼272.6 Hz), 81.47, 80.26, 72.35, 29.24, 22.40, 22.24; HRMS (ESI) m/z
calcd for C17H19F3O5 [MþH]þ: 383.1082, found: 383.1072.
4.3.4. (2R,3R)-Isopropyl 2-((E)-3-chlorostyryl)-2,3-dihydroxy-4-
oxopentanoate (11h). Yield 40.7 mg, 85%; light yellow solid, mp
74e76 ꢀC; 85% ee, 10:1 dr [determined by HPLC analysis: chiral OD-
4.3.9. (2R,3R)-Isopropyl 2,3-dihydroxy-2-((E)-4-methylstyryl)-4-
oxopentanoate (11m). Yield 32.0 mg, 73%; white solid, 88e91 ꢀC;
87% ee, 15:1 dr [determined by HPLC analysis: chiral OD-H, hexane/
H, hexane/isopropanol¼95:5, 0.8 mL/min, 254 nm UV detector;
25
tR¼17.97 min (minor), tR¼19.16 min (major); [
a
]
D
ꢁ88.39 (c 0.56,
isopropanol¼95:5, 0.8 mL/min, 254 nm UV detector; tR¼16.49 min
CHCl3)]; 1H NMR (400 MHz, CDCl3)
d
7.42 (s, 1H), 7.28e7.27 (m, 3H),
(minor), tR¼19.95 min (major); [
a]
ꢁ210.52 (c 0.56, CHCl3)]; 1H
25
D
6.93 (d, J¼15.8 Hz, 1H), 6.51 (d, J¼15.8 Hz, 1H), 5.18e5.11 (m, 1H),
NMR (400 MHz, CDCl3)
d
7.34 (d, J¼7.6 Hz, 2H), 7.17 (d, J¼7.7 Hz,
4.57 (d, J¼6.9 Hz,1H), 4.00 (d, J¼6.9 Hz,1H), 3.88 (s,1H), 2.19 (s, 3H),
2H), 6.96 (d, J¼15.8 Hz, 1H), 6.44 (d, J¼15.8 Hz, 1H), 5.18e5.12 (m,
1H), 4.59 (d, J¼6.8 Hz, 1H), 3.99 (d, J¼6.8 Hz, 1H), 3.83 (s, 1H), 2.36
(s, 3H), 2.20 (s, 3H), 1.34 (dd, J¼17.1, 6.2 Hz, 6H); 13C NMR (101 MHz,
1.34 (dd, J¼13.6, 6.3 Hz, 6H); 13C NMR (101 MHz, CDCl3)
d 205.79,
172.05, 138.34, 135.40, 131.51, 130.69, 128.95, 127.63, 127.18, 125.94,
81.48, 80.24, 72.28, 29.33, 22.44, 22.26; HRMS (ESI) m/z calcd for
CDCl3) d 205.94, 172.36, 139.03, 133.75, 132.62, 130.13, 127.43,
C
16H19ClO5 [MþNa]þ: 349.0819, found: 349.0812.
125.01, 81.54, 80.32, 72.00, 29.41, 22.42, 22.28, 21.90; HRMS (ESI) m/
z calcd for C17H22O5 [MþNa]þ: 329.1365, found: 329.1358.
4.3.5. (2R,3R)-Isopropyl 2-((E)-4-bromostyryl)-2,3-dihydroxy-4-
oxopentanoate (11i). Yield 46.6 mg, 82%; white solid, mp
98e100 ꢀC; 90% ee, 10:1 dr [determined by HPLC analysis: chiral
OD-H, hexane/isopropanol¼95:5, 0.8 mL/min, 254 nm UV detector;
4.3.10. (2R,3R)-Isopropyl 2,3-dihydroxy-2-((E)-3-methylstyryl)-4-
oxopentanoate (11n). Yield 37.3 mg, 85%; light yellow solid,
66e69 ꢀC; 86% ee, 14:1 dr [determined by HPLC analysis: chiral OD-

W. Guo et al. / Tetrahedron 70 (2014) 6561e6568
6567
H, hexane/isopropanol¼95:5, 0.8 mL/min, 254 nm UV detector;
[determined by HPLC analysis: chiral AD-H, hexane/iso-
25
tR¼14.38 min (minor), tR¼20.94 min (major); [
a]
ꢁ171.32 (c 0.6,
propanol¼97:3, 0.6 mL/min; 254 nm UV detector; tR¼73.1 min
D
CHCl3)]; 1H NMR (400 MHz, CDCl3)
d
7.28e7.24 (m, 3H), 7.12e7.11
(minor), tR¼100.6 min (major)]; [
a
]
25 ꢁ138.32 (c 0.9, CHCl3); 1H NMR
D
(m, 1H), 6.96 (d, J¼15.8 Hz, 1H), 6.48 (d, J¼15.8 Hz, 1H), 5.18e5.10
(m, 1H), 4.60 (d, J¼6.8 Hz, 1H), 4.02 (d, J¼6.8 Hz, 1H), 3.86 (s, 1H),
2.37 (s, 3H), 2.21 (s, 3H), 1.34 (dd, J¼15.9, 6.3 Hz, 6H); 13C NMR
(400 MHz, CDCl3)
d
7.60 (s, 1H), 7.42 (d, J¼8.1 Hz, 1H), 7.33 (d,
J¼8.1 Hz, 1H), 7.23 (m, 1H), 6.93 (d, J¼15.8 Hz, 1H), 6.52 (d, J¼15.8 Hz,
1H), 4.59 (d, J¼6.7 Hz, 1H), 4.35 (m, 2H), 4.00 (d, J¼6.8 Hz, 1H), 3.82
(s, 1H), 2.20 (s, 3H), 1.37 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
(101 MHz, CDCl3)
d 205.97, 172.32, 139.07, 136.44, 132.87, 129.83,
129.34, 128.20, 125.80, 124.68, 81.54, 80.36, 72.07, 29.46, 22.45,
d 205.12, 171.96, 137.95, 131.35, 130.96, 130.42, 129.52, 126.90, 125.89,
22.29, 22.07; HRMS (ESI) m/z calcd for
329.1365, found: 329.1360.
C
17H22O5 [MþNa]þ:
123.04, 80.90, 79.82, 63.48, 28.82, 14.24; HRMS (ESI) m/z calcd for
C
15H17BrO5 [MþNa]þ: 379.0157, found: 379.0154.
4.3.11. (2R,3R)-Isopropyl 2,3-dihydroxy-4-oxo-2-((E)-2-(thiophen-2-
yl)vinyl)pentanoate (11o). Yield 33.4 mg, 79%; yellow solid, mp
80e82 ꢀC; 84% ee, 12:1 dr [determined by HPLC analysis: chiral OD-
4.3.16. (2R,3R)-Ethyl 2-(3-bromophenethyl)-2,3-dihydroxy-4-
oxopentanoate (12s). The product was prepared by using a hydro-
gen balloon at large scale (2.0 mmol). Yield 95%, colorless oil. 1H
H, hexane/isopropanol¼95:5, 0.8 mL/min, 254 nm UV detector;
NMR (400 MHz, CDCl3) d 7.18e7.31 (m, 4H), 4.19e4.30 (m, 3H), 3.79
25
tR¼17.77 min (major), tR¼19.38 min (minor)]; [
a]
ꢁ140.21 (c 0.7,
(s, 1H), 3.71 (d, J¼8.8 Hz, 1H), 2.79e2.86 (m, 1H), 2.42e2.50 (m, 1H),
D
CHCl3). 1H NMR (400 MHz, CDCl3)
d
7.23 (d, J¼5.0 Hz, 1H), 7.09 (d,
2.33 (s, 3H), 2.08e2.31 (m, 2H), 1.32 (t, J¼7.2 Hz, 3H); 13C NMR
J¼15.6 Hz, 1H), 7.04e6.99 (m, 2H), 6.31 (d, J¼15.6 Hz, 1H), 5.17e5.11
(m, 1H), 4.56 (d, J¼6.8 Hz, 1H), 3.98 (d, J¼6.8 Hz, 1H), 3.84 (s, 1H),
2.21 (s, 3H), 1.33 (dd, J¼14.2, 6.3 Hz, 6H); 13C NMR (101 MHz, CDCl3)
(101 MHz, CDCl3) d 209.10, 174.81, 141.65, 129.14, 129.12, 126.81,
80.96, 79.62, 63.40, 38.05, 30.33, 29.21, 14.84; [
a
]
D
25 ꢁ25.31 (c 0.85,
CHCl3); HRMS (ESI) m/z calcd for C11H19BrO5 [MþNa]þ: 381.0314,
d
205.84, 172.10, 141.50, 128.40, 127.85, 126.02, 125.98, 125.31, 81.41,
found: 381.0323.
80.04, 72.17, 29.38, 22.41, 22.27; HRMS (ESI) m/z calcd for
C
26H48N4O [MþH]þ: 433.3906, found: 433.3899; HRMS (ESI) m/z
4. 3.17. (2R, 3S, 4S)-Ethyl 2-((E)-3-bromostyryl)-2, 3, 4-
trihydroxypentanoate (13s). To a cold (0 ꢀC), stirred solution of
the adduct 11s (0.2 mmol, 1.0 equiv) in dry THF (0.1 M) was added
a solution of catechol borane in THF (1.0 M, 2.2 equiv). The resulting
mixture was allowed to warm gradually to room temperature and
was then stirred until complete consumption of starting adduct 11s
was observed by TLC analysis. The mixture was then diluted with
MeOH (to 0.05 M) and a solution of saturated aqueous sodium
tartrate was added. The biphasic mixture was stirred vigorously for
1.5 h, after which time the aqueous layer was removed and
extracted three times with ether. The combined organic layers were
dried over NaSO4, concentrated under reduced pressure, and the
crude product was purified by column chromatography to get the
desired product as colorless oil, 45% isolated yield (petroleum
ether/ethyl acetate¼1:1, Rf¼0.4, dr>30:1 by crude 1H NMR analy-
calcd for C14H18O5S [MþNa]þ: 321.0773, found: 321.0767.
4.3.12. (R,E)-Methyl 2-hydroxy-2-((R)-1-hydroxy-2-oxopropyl)dec-
3-enoate (11p). Yield 27.7 mg, 65%, inseparable diastereomers mix-
ture! Colorless oil; 75% ee, 8:1 dr [determined by HPLC analysis:
chiral AD-H, hexane/isopropanol¼98:2, 0.7 mL/min, 215 nm UV
detector; tR¼46.83 min (minor), tR¼58.79 min (major)]; 1H NMR
(400 MHz, CDCl3)
d
6.14e6.06 (m, 1H), 5.77 (d, J¼15.4 Hz, 1H), 4.47
(d, J¼5.6 Hz, 1H), 3.98 (d, J¼5.6 Hz, 1H), 3.85 (s, 3H), 3.61 (s, 1H),
2.21 (s, 3H), 2.11 (dt, J¼14.5, 7.3 Hz, 2H), 1.41e1.38 (m, 2H),
1.27e1.25 (m, 10H), 0.88 (t, J¼6.3 Hz, 3H); 13C NMR (101 MHz,
CDCl3)
d 205.30, 173.21, 134.68, 125.89, 80.77, 79.58, 53.67, 32.24,
31.71, 29.79, 29.02, 28.93, 28.90, 22.69, 14.16; HRMS (ESI) m/z calcd
for C14H24O5 [MþNa]þ: 295.1521, found: 295.1508.
sis). 1H NMR (400 MHz, CDCl3)
d 7.54 (s, 1H), 7.38e7.40 (m, 1H),
4.3.13. (2R,3R)-methyl 2-((E)-2-cyclohexylvinyl)-2,3-dihydroxy-4-
oxopentanoate (11q). Yield 30.8 mg, 57% colorless oil; inseparable
diastereomers mixture! 64% ee, 9:1 dr [determined by HPLC analy-
sis: chiral AD-H, hexane/isopropanol¼97:3, 0.7 mL/min, 215 nm UV
detector; tR¼37.00 min (minor), tR¼45.22 min (major)]; 1H NMR
7.27e7.30 (m, 1H), 7.17e7.21 (m, 1H), 6.82e6.86 (d, J¼15.6 Hz, 1H),
6.36e6.40 (d, J¼15.6 Hz, 1H), 4.25e4.39 (m, 2H), 4.08 (s, 1H),
3.96e4.04 (m, 2H), 2.74 (d, J¼9.6 Hz, 1H), 2.31 (d, J¼4.8 Hz, 1H), 1.35
(t, J¼6.8 Hz, 3H), 1.27 (d, J¼6.4 Hz, 3H); 13C NMR(101 MHz, CDCl3)
d173.48, 138.19, 131.07, 130.27, 129.57, 129.21, 128.09, 125.67, 122.96,
(400 MHz, CDCl3)
d
6.04 (dd, J¼15.6, 6.9 Hz, 1H), 5.71 (d, J¼15.6 Hz,
80.52, 77.37, 69.27, 63.31, 19.50, 14.20.
1H), 4.46 (d, J¼6.6 Hz, 1H), 3.99 (d, J¼6.6 Hz, 1H), 3.84 (s, 3H), 3.60
(s, 1H), 2.19 (s, 3H), 2.08e2.01 (m, 1H), 1.73e1.64 (m, 6H), 1.29e1.05
4.3.18. (3R,4R)-5,5,5-Trifluoro-3,4-dihydroxy-4-phenylpentan-2-
one. Yield 70%, white solid, inseparable diastereomers mixture! 83%
ee, 6:1 dr [determined by HPLC analysis: chiral OD-H, hexane/iso-
propanol¼90:10, 0.8 mL/min, 215 nm UV detector; tR¼12.70 min
(major), tR¼14.34 min (minor)]; 1H NMR (400 MHz, CDCl3)
(m, 6H); 13C NMR (101 MHz, CDCl3)
d 205.82, 173.83, 140.42, 124.22,
81.44, 80.19, 54.24, 41.02, 33.19, 33.11, 29.71, 26.66, 26.55; HRMS
(ESI) m/z calcd for C14H22O5 [MþNa]þ: 293.1365, found: 293.1358.
4.3.14. (R,E)-Methyl 2-hydroxy-2-((R)-1-hydroxy-2-oxopropyl)-5-
methylhex-3-enoate (11r). Yield 26.7 mg, 58%, colorless oil, in-
separable diastereomers mixture! 66% ee, 10:1 dr [determined by
HPLC analysis: chiral OD-H, hexane/isopropanol¼98:2, 0.6 mL/min,
215 nm UV detector; tR¼34.3 min (major), tR¼48.6 min (minor)]; 1H
d
7.65e7.69 (m, 2H), 7.40e7.50 (m, 3H), 4.84 (d, J¼4.8 Hz, 1H), 4.21
(d, J¼4.8 Hz,1H), 3.75 (s,1H), 1.56 (s, 3H); 13C NMR(101 MHz, CDCl3)
d
206.07, 134.14, 129.62, 129.05, 126.04, 123.23 (q, J¼287.8 Hz),
79.20, 78.81 (q, J¼25.6 Hz), 26.23; HRMS (ESI) m/z calcd for
C
11H11F3O3 [MþNa]þ: 271.0558, found: 211.0546.
NMR (400 MHz, CDCl3)
d
6.06 (dd, J¼15.5, 6.8 Hz, 1H), 5.71 (d,
J¼15.5 Hz, 1H), 4.47 (d, J¼6.6 Hz, 1H), 3.99 (d, J¼6.6 Hz, 1H), 3.85 (s,
3H), 3.62 (s, 1H), 2.43e2.33 (m, 1H), 2.19 (s, 3H), 1.01 (dd, J¼9.8,
Acknowledgements
4.9 Hz, 6H); 13C NMR (101 MHz, CDCl3)
d
205.82, 173.81, 141.56,
We thank the financial support from the Natural Science
Foundation of China (21002100) and National Basic Research Pro-
gram of China (2010CB833300).
123.86, 81.43, 80.11, 54.25, 31.45, 29.64, 22.71, 22.55; HRMS (ESI) m/
z calcd for C11H18O5 [MþNa]þ: 253.1052, found: 253.1046.
4.3.15. (2R,3R)-Ethyl 2-((E)-3-bromostyryl)-2,3-dihydroxy-4-
oxopentanoate (11s). Large-scale synthesis of adduct 4s: 1.0 g, 80%
yield (for anti diastereomer), white crystal, mp 122e124 ꢀC; 86% ee
(95% ee after single recrystallization from DCM/Hexane, 53% yield).
Supplementary data
Copies of 1H NMR, 13C NMR spectra and HPLC chromatograms of
all compounds. CCDC 965287 can be obtained free of charge via

6568
W. Guo et al. / Tetrahedron 70 (2014) 6561e6568
2011, 13, 6106; (c) Zhang, L.; Lee, M. M.; Lee, S. M.; Lee, J.; Cheng, M.; Jeong, B. S.;
Park, H. G.; Jew, S. S. Adv. Synth. Catal. 2009, 351, 3063.
12. (a) Lin, J.; Tian, H.; Jiang, Y. J.; Huang, W. B.; Zheng, L. Y.; Zhang, S. Q. Tetrahe-
dron: Asymmetry 2011, 22, 1434; (b) a similar catalyst was reported by Alten-
bach, H. J. et al. see Tang, G. K.; Gun, U.; Altenbach, H. J. Tetrahedron 2012, 68,
10230.
www.ccdc.cam.ac.uk/data_request/cif or by emailing data_-
request@ccdc.cam.ac.uk. Supplementary data associated with this
article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2014.07.015.
13. (a) Zhang, B.; Jiang, Z.; Zhou, X.; Lu, S.; Li, J.; Liu, Y.; Li, C. Angew. Chem., Int. Ed.
2012, 51, 13159; (b) Guo, W.; Wang, X.; Zhang, B.; Shen, S.; Zhou, X.; Wang, P.;
Liu, Y.; Li, C. Chem. Eur. J. 2014, 20, 8545.
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