A highly enantio- and diastereoselective direct aldol reaction in aqueous medium catalyzed by thiazolidine-based compounds

Article abstract of DOI:10.1016/j.tetasy.2015.04.010

Taking l-aminoacids as starting materials, a new set of enantiopure thiazolidine-based organocatalysts were prepared using a simple synthetic approach and successfully applied in the asymmetric direct aldol reaction between various cyclic ketones and aldehydes in a saturated aqueous medium. The aldol adducts were obtained with excellent enantioselectivity (up to >99% ee) and diastereoselectivity (dr >20:1).

Full text of DOI:10.1016/j.tetasy.2015.04.010

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A highly enantio- and diastereoselective direct aldol reaction
in aqueous medium catalyzed by thiazolidine-based compounds
⇑
Raoní Scheibler Rambo, Caroline Gross Jacoby, Tiago Lima da Silva, Paulo Henrique Schneider
Instituto de Química, Universidade Federal do Rio Grande do Sul (UFRGS), PO Box 15003, 91501-970 Porto Alegre-RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Taking L-aminoacids as starting materials, a new set of enantiopure thiazolidine-based organocatalysts
Received 30 March 2015
Accepted 15 April 2015
Available online xxxx
were prepared using a simple synthetic approach and successfully applied in the asymmetric direct aldol
reaction between various cyclic ketones and aldehydes in a saturated aqueous medium. The aldol adducts
were obtained with excellent enantioselectivity (up to >99% ee) and diastereoselectivity (dr >20:1).
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, our group has developed a new class of thiazolidine-
based organocatalysts, which are readily obtained from L-cysteine
Asymmetric organocatalysis, which is based on use of small
organic molecules in the absence of transition metals, is now a
well-established research area and recognized as the third column
of organic synthesis due to its versatility and efficiency. To date,
more than 300 reactions and methodologies have been developed
using organocatalyzed processes.1 Since the seminal article pub-
and successfully applied them in the direct asymmetric aldol reac-
tion between propanone and a variety of aldehydes 3d–g (Fig. 1).9
In this context and in connection with our continuing interest in
the development and application of new organocatalysts, we
now report the synthesis of three new thiazolidine-based com-
pounds 3a–c (Fig. 1) in an attempt to improve the activity and
selectivity of thiazolidine-based organocatalysts. We have also
expanded the application of these compounds by evaluating their
catalytic activity in the direct asymmetric aldol reaction between
various cyclic ketones and aldehydes in an aqueous medium.
lished by List, Barbas et al.,2 which reported the use of
L-proline
to catalyze the direct intermolecular asymmetric aldol reaction,
this research area has experienced an exponential growth. Great
effort has been devoted to the development of new organocatalysts
and organocatalytic processes that can be used toward the
synthesis of lead products in high yield and stereoselectivity
including the synthesis of natural products and compounds with
interesting biological properties.1a–g
2. Results and discussion
The organocatalysts 3a–f were synthesized via a short and high
yielding sequence using L-amino acids as the starting materials.
The amino acid L-proline has been intensively studied and used
to catalyze more than ten different reactions and has therefore
achieved a ‘privileged catalyst’ status.3 Consequently, over the past
few years, a great deal of attention has been devoted to the use of
naturally occurring amino acids in organocatalysis due to their low
cost and availability in an enantiopure form.4
Most importantly, this synthetic strategy can readily generate a
high degree of structural diversity, which is important for the sys-
tematic optimization of the catalysts structure.
L
-Cysteine was initially reacted with formaldehyde and subse-
quently protected with Boc2O to give the unsubstituted thiazo-
lidine carboxylic acid 1a (Scheme 1). In order to study the
influence of substituents on the heterocyclic moiety, compound
1b was also synthesized by refluxing L-cysteine in propanone fol-
lowed by protection with Boc2O.
A double Grignard addition or reduction of an aminoester
afforded the desired range of aminoalcohols, which were reacted
with the thiazolidine carboxylic acids 1a and 1b in the presence
of stoichiometric amounts of ClCO2Et and NMM to give the corre-
sponding amides 2a–c (Scheme 2). In order to understand the role
of the different substituents (R, R0, and R00), different amino acids
Further studies reported by Barbas et al.2a have shown that (R)-
thiazolidine-4-carboxylic acids can also promote the aldol reaction
with high enantioselectivity. However, the use of this type of
heterocycle as a chiral modifier in organocatalysis has been
rarely reported.2,5 Despite the lack of literature precedent, during
the course of our work in the field of asymmetric catalysis we have
reported the successful use of thiazolidines as chiral ligands in
several organometallic reactions.6–8
⇑
Corresponding author. Tel.: +55 51 3308 9636; fax: +55 51 3308 7304.
E-mail address: paulos@iq.ufrgs.br (P.H. Schneider).
were used including L-methionine and L-cysteine for compounds
http://dx.doi.org/10.1016/j.tetasy.2015.04.010
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Rambo, R. S.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.04.010

2
R. S. Rambo et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
S
Ph
HS
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
N
H
S
N
H
N
H
S
S
NH
OH
NH
OH
NH
OH
3a
3b
3c
Ph
Ph
S
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
N
H
N
H
N
H
N
H
S
S
S
S
NH
OH
NH
OH
NH
OH
NH
OH
3d
3e
3f
3g
Figure 1. Thiazolidine-based organocatalysts 3a–g.
Table 1
O
O
Optimization of the reaction conditionsa
i, ii or iii, iv
OH
S
R
HS
OH
NH2.HCl
Ph
Ph
N
O
Boc
R
Ph
N
1a: R=H
1b: R=Me
S
H
L-cisteine
NH
OH
O
O
O
OH
3d
Scheme 1. Synthesis of the thiazolidine carboxylic acids 1a–b. Reagents and
conditions: (i) 37% HCHO, 1 M NaOH; (ii) Boc2O, 1 M NaOH, 1,4-dioxane/H2O (95%);
(iii) Me2CO, reflux; (iv) Boc2O, DIPEA, MeCN (40%).
H
4
5
6
Entry
Catalyst
(mol %)
Time
(h)
Temp
(°C)
Yieldb
(%)
eec
(%)
drd
(anti/syn)
3a and 3b, respectively, and L-phenylalanine for compound 3c.
Removal of the Boc group delivered the desired organocatalysts
3a–c in good overall yield. Compounds 3d and 3g (Fig. 1) were syn-
thesized using the same synthetic strategy. All spectroscopic data
are in accordance with those reported in the literature.9
1
2
3
4
5
6
7
8
10
10
10
10
10
5
24
48
72
rt
rt
rt
rt
rt
rt
rt
40
16
23
25
58
66
24
55
54
99
99
99
99
99
92
80
94
10:1
10:1
10:1
10:1
10:1
>20:1
>20:1
8:1
96
With the target compounds 3a–c in hand, together with the
known organocatalysts 3d–f, we focused our attention toward
the optimization of the aldol reaction with an aim of controlling
the stereochemistry of the two stereocenters formed during the
reaction. As a model reaction, we elected to investigate the aldol
reaction between cyclohexanone and benzaldehyde catalyzed by
compound 3d. Organocatalyst 3d had furnished the best results
in a previously reported study9 and the results depicted in Table 1.
Initially, we investigated the effect of catalyst loading, reaction
time, and temperature on the yield, diastereomeric ratio (dr) and
enantiomeric excess (ee). As expected, lower yields were obtained
with shorter reaction times (Table 1, entries 1–5). By either
increasing or decreasing the catalyst loading from 10 mol %,
120
120
120
120
15
10
a
Reaction performed with 1.0 mL of cyclohexanone, 1.0 mmol (0.101 mL) of
benzaldehyde and 5–15 mol % of organocatalyst 3d.
b
Isolated yield.
c
Determined by HPLC using chiral stationary phase.
Determined by 1H NMR spectroscopy of the crude reaction mixture.
d
inferior results were achieved. In the case of 5 mol % of catalyst
3d, a dramatic decrease in the yield and ee was observed
(Table 1, entries 6 and 7). Using 15 mol % of catalyst, no significant
O
O
R'
R''
R''
1) ClCOOEt, NMM, DCM
OH
N
H
S
S
R''
2)
R''
N
N
OH
R'
R
R
Boc
Boc
OH
R
R
NH2
1a-b
2a-c
75-85%
O
R'
R''
R''
3a: R = H, R' = (CH2)2SMe, R'' = Ph
1) 4.5M HCl/AcOEt
2) K2CO3, DCM
60-80%
N
H
3b:
3c:
R = H, R' = CH2SH, R'' = Ph
R = Me, R' = Bn, R'' = Ph
S
N
OH
H
R
R
3a-c
Scheme 2. Synthesis of organocatalysts 3a–c.
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R. S. Rambo et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
Table 3
increase in product yield was observed, however a great reduction
in ee was observed. No changes in product yield were observed
when the reaction was performed at 40 °C, but in terms of the
stereoselectivity of the reaction, the results were poor (Table 1,
entry 8).
Direct asymmetric aldol reaction between cyclohexanone and benzaldehyde cat-
alyzed by organocatalysts 3a–fa
O
O
O
OH
10 mol% 3a-f
H
After screening the experimental parameters, we performed the
reaction with the optimized conditions using organocatalyst 3d in
different polar and non-polar solvents as well as in aqueous sys-
tems (Table 2). Performing the reaction in CH2Cl2 or toluene leads
to a dramatic reduction in the product yield and stereoselectivity
(Table 2, entries 2 and 3). Surprisingly, the use of DMSO, a broadly
used solvent in organocatalytic systems,4 did not promote the
reaction and trace amounts of product were obtained (Table 2,
entries 4 and 7). When considering the literature precedent, we
discovered that the use of this type of organocatalyst in the direct
aldol reaction has been shown to be influenced, in terms of the
stereoselectivity of the reaction, by the use of a reaction system
with equal amounts of water or brine and ketone.5,11
Subsequently, we performed the reaction using water itself or
aqueous solvent systems and good results were achieved
(Table 2, entries 5 and 6 compared with entries 8 and 9). Indeed
when brine was used as the solvent, an excellent ee (99%) and
excellent dr (>20:1 (anti/syn)) were obtained (Table 2, entry 9).
Once we established the optimized catalyst loading and the
reaction conditions, we evaluated the different characteristics of
compounds 3a–f in regard to their polarity, solubility, and
hydrophobicity or hydrophilicity, in order to identify an organocat-
alyst with superior performance. For this purpose we used the two
best reaction conditions: (1) using the ketone as solvent (Table 2,
entries 1 and 2) using a brine/ketone mixture as the solvent
(Table 2, entry 9). The results are summarized in Table 3 (please
note the results in the parenthesis refer to reactions performed
using a brine/ketone solvent system).
120 h
r.t.
4
5
6
Entry
Catalyst
Yieldb (%)
35 (69)
% eec
drd (anti/syn)
S
O
Ph
Ph
Ph
1
90 (99)
19:1 (19:1)
N
H
S
N
OH
H
3a
HS
O
Ph
N
H
S
N
2
3
46 (35)
42 (20)
94 (99)
36 (96)
>20:1 (>20:1)
OH
H
3b
Ph
O
Ph
Ph
N
H
S
4:1 (19:1)
N
OH
Me
H
Me
3c
Ph
O
Ph
Ph
N
H
S
4
5
6
66 (64)
75 (40)
25 (33)
99 (99)
92 (99)
64 (92)
10:1 (>20:1)
10:1 (>20:1)
>20:1 (>20:1)
N
OH
H
3d
We observed that the catalysts possessing polar hydrophilic
groups on the aminoalcohol moiety furnished the desired pro-
duct in moderate yields and with high ee and dr (Table 3, entries
1 and 2). The presence of a gem-dimethyl group on the hetero-
cycle in catalyst 3c caused a dramatic reduction in the reaction
yield, which was attributed to difficult enamine formation
O
Ph
Ph
N
H
S
S
N
N
OH
OH
H
3e
Ph
O
N
H
Table 2
Solvent screena
H
Ph
3f
O
Ph
Ph
N
a
Reaction performed with 1.0 mL of cyclohexanone, 1.0 mmol of benzaldehyde,
and 0.1 mmol of organocatalyst.
S
H
b
NH
OH
Isolated yield.
O
O
O
OH
c
10 mol% 3d
Determined by HPLC using chiral stationary phase.
Determined by 1H NMR spectroscopy of the crude reaction mixture. The results
d
H
120h, r.t.
in the parenthesis refer to reactions performed using a brine/ketone solvent system.
4
5
6
(Table 1, entries 3 and 4). A similar result was found with the
organocatalyst with no gem-diphenyl group on the amino alco-
hol moiety (Table 1, entry 6). According to previous reports,
the gem-diaryl group plays a crucial role in the catalytic sys-
tem.10 These substituents act by facilitating the formation of cyc-
lic intermediates through the Thorpe–Ingold effect. In addition,
for the case of alcohols, this group contributes to an increase
in the acidity of the hydroxyl group, which was required in
the formation of hydrogen bonds. The best results were obtained
with organocatalysts 3d and 3e, which contain hydrophobic
groups (benzyl and isopropyl groups, respectively). Although cat-
alyst 3e furnished the aldol adduct in the highest yield, the
stereoselectivity of the reaction was better using catalyst 3d
(entries 4 and 5).
Entry
Solvent
Yieldb (%)
eec (%)
drd (anti/syn)
1
2
3
4
5
6
7
8
9
4
66
15
20
99
71
60
—
94
99
—
10:1
6:1
8:1
CH2Cl2
PhMe
DMSO
H2O
Traces
59
62
Traces
60
—
14:1
14:1
—
10:1
>20:1
Brine
DMSO–4 (1:1)
H2O–4 (1:1)
Brine–4 (1:1)
97
99
64
a
Reaction performed with 1.0 mL of solvent or solvent combination, 1.0 mmol of
benzaldehyde (0.101 mL) and 10 mol % (0.1 mmol, 0.042 g) of organocatalyst 3d.
b
Isolated yield.
c
Determined by HPLC using chiral stationary phase.
Determined by 1H NMR spectroscopy of the crude reaction mixture.
d
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R. S. Rambo et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Table 4
S
S
Reaction scope: aldehydes and cyclic ketonesa
O
O
O
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
N
O
H
H
Ph
O
O
H
H
N
H
O
S
Ar
H
NH
OH
Ar
OH
O
O
H
O
10 mol% 3d
Ar
unfavored TS
Figure 2. Proposed transition states.
favored TS
r.t
Ar
H
4a-c
5a-k
6a-k
drd
Entry
Ketone
(n)
Aldehyde
(Ar)
Time
(h)
Yieldb
(%)
%
As expected, performing the reaction in a ketone–brine solvent
eec
(anti/syn)
system gave improved results in terms of the reaction yield and
stereoselectivity for the majority of the catalysts studied.
Notably, an increase in ee was observed for all the catalysts, up
to 99% ee in most cases and no less than 92% ee (catalyst 3f).
Also the dr values showed a remarkable improvement for catalysts
3c–e, up to >20:1 and no less than 19:1. The reaction yield
remained in the same range for the majority of the catalysts with
the exception of catalyst 3a where a considerable increase in yield
from 35% to 69% was observed while when catalyst 3e was used a
decrease in yield from 75% to 40%, which was attributed to its low
solubility in an aqueous medium was obtained.
1
2
3
4
5
6
7
8
4a (2)
4a (2)
4a (2)
4a (2)
4a (2)
4a (2)
4a (2)
4a (2)
4a (2)
4b (1)
4c (3)
Ph
p-Me-Ph
p-MeO-Ph
p-Cl-Ph
p-Br-Ph
p-CN-Ph
o-NO2-Ph
m-NO2-Ph
p-NO2-Ph
p-NO2-Ph
p-NO2-Ph
120
120
120
120
120
24
24
24
24
24
6a: 66
6b: 25
6c: 15
6d: 84
6e: 60
6f: 96
6g: 97
6h: 95
6i: 90
99
>99
98
99
99
98
>99
98
98
90
—
>20:1
>20:1
>20:1
>20:1
8:1
>20:1
>20:1
10:1
10:1
2:1
9
10
11
6j: 97
6k: trace
120
—
a
Reaction performed with 0.5 mL of cyclic ketone, 0.5 mL of brine, 1.0 mmol of
Based on these experimental results and literature precedent,
we propose that the stereoselectivity observed during the direct
aldol reaction catalyzed by 3a–f can be described by the transition
state model depicted in Figure 2.10,12 After enamine formation by
the catalyst and ketone, the position of the aldehyde can be ori-
ented via hydrogen bonding interactions. In this way, the C–C bond
formation takes place from the re face of the aldehyde. The pres-
ence of the gem-diphenyl group on the amino alcohol moiety
restricts the conformation of the transition state and makes the
hydroxyl group a better hydrogen bond donor (Table 3, entries 4
and 6). Furthermore, the beneficial effect of water in the asymmet-
ric aldol reaction was attributed to improved catalyst turnover due
to faster hydrolysis of the intermediates in the enamine catalytic
cycle and the suppression of catalyst inhibition.
Having established the optimal reaction conditions, the scope
and limitations of the direct aldol reaction catalyzed by 3d were
also examined (Table 4). The optimal reaction conditions were
applied in the organocatalytic reaction and a wide range of aro-
matic aldehydes were found to react smoothly with cyclic ketones
to give their corresponding aldol adducts with good to excellent
results. The results listed in Table 4 confirm that ligand 3d was a
suitable catalyst for this asymmetric reaction.
Aldehydes with strong electron-donating groups in the para
position, such as methyl and methoxyl groups (Table 4, entries 2
and 3, respectively), lead to a low yield of the desired product even
when prolonged reaction times were used. However, excellent
enantioselectivity (up to 99% ee for p-tolualdehyde) and good to
excellent diastereoselectivity were observed. In the case of para-
halogenated aldehydes, the aldol addition product was obtained
in moderate to good yield after 120 h with excellent ee and dr
(Table 4, entries 4 and 5).
aldehyde and 10 mol % (0.1 mmol, 0.042 g) of organocatalyst 3d.
b
Isolated yield.
c
Determined by HPLC using chiral stationary phase.
Determined by 1H NMR spectroscopy of the crude reaction mixture.
d
the reaction was performed with a larger cyclic ketone, cyclohep-
tanone (Table 4, entry 11), no product was isolated. This was
attributed to the formation of an enamine that provided greater
steric repulsion to the aldehyde (see the transition state shown
in Fig. 2).
3. Conclusion
To summarize, three new thiazolidine amides derived from dif-
ferent L-amino alcohols were synthesized using a simple synthetic
approach. A wide variety of substituents can be incorporated into
the compounds and allowed us to explore the influence of their
stereoelectronic effects in order to discover an efficient catalytic
system. All the organocatalysts were evaluated for their ability to
catalyze the direct aldol reaction between a variety of aromatic
aldehydes and cyclic ketones. The results demonstrated that the
organocatalyst 3d was very efficient and furnished the desired
aldol adducts with excellent enantioselectivity (up to 99% ee)
and diastereoselectivity [dr = 99:1 (anti/syn)]. Expanding the scope
of this organocatalyst in other asymmetric transformations is cur-
rently underway in our laboratory.
4. Experimental
4.1. General methods
The use of aromatic aldehydes with strong electron-withdraw-
ing groups such as nitro or cyano groups (Table 4, entries 6–9), lead
to a dramatic decrease in the reaction time and the products were
obtained in an almost quantitative yield after 24 h. Regardless of
the position and chemical nature of the substituent, the stereose-
lectivity obtained was excellent, with enantioselectivities >98%
ee and diastereoselectivities between 10:1 and >20:1.
Using a smaller cyclic ketone, cyclopentanone (Table 4, entry
10), the organocatalyst was also effective giving the aldol product
in excellent yield (90%) after 24 h and good enantioselectivity (90%
ee) although the diastereoselectivity was lower (dr = 2:1). When
The 1H NMR, 13C NMR, 2D-COSY NMR, and 2D-HMQC NMR
spectra were recorded on 300 MHz spectrometers Varian Inova
300 and Varian VNMRS 300. Chemical shifts (d) are expressed in
ppm downfield from TMS as internal standard in spectra made in
CDCl3. Coupling constants are reported in Hz. All enantiomeric
excesses were obtained from HPLC using chiral stationary phase
(Chiralcel OD-H or OJ-H columns and Chiralpak AD-H or AS-H col-
umns) in a Shimadzu LC-20AT chromatograph. Optical rotations
were obtained in a Perkin Elmer Polarimeter 341. Infrared spectra
were obtained in a Varian 640-IR spectrometer. All the column
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R. S. Rambo et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
chromatography separations were done by using silica gel Fluka,
100–200 Mesh. Solvents were purified by usual methods.13 Other
reagents were obtained from commercial source and used without
further purification. The organic extracts were dried over anhy-
drous sodium sulfate. Evaporation of solvent was performed under
reduced pressure. Brine refers to saturated solution of NaCl in
water at 25 °C.
as a white solid. Yield: 50%. Mp 193–196 °C. [
a
]
20 = ꢁ98 (c 1,
D
CH2Cl2). IR (FT-IR/ATR, cmꢁ1): 1517, 1656, 2960, 2980, 3320. 1H
NMR (300 MHz, CDCl3) d: 7.71 (m, 2H), 7.58 (m, 2H), 7.39 (m,
2H), 7.24 (m, 7H), 7.17 (m, 3H), 5.40 (br s, 1H), 4.84 (m, 1H),
3.81 (m, 1H), 3.17 (m, 2H), 2.91 (dd, 2H, J = 3.4 Hz, J = 13.6 Hz),
2.79 (dd, 2H, J = 8.5 Hz, J = 11.9 Hz), 2.09 (br s, 1H), 1.63 (br s,
1H), 1.43 (s, 3H), 0.97 (s, 3H). 13C NMR (CDCl3, 75.5 MHz) d:
172.1, 145.7, 144.9, 139.1, 129.1, 128.8, 128.3, 127.4, 126.6,
126.2, 125.8, 125.4, 80.9, 80.2, 67.6, 60.8, 59.4, 36.1, 30.3, 28.3.
HRMS calculated for [C27H30N2O2S+Na]+: 469.5935, obtained:
469.5940.
4.2. General procedure for the synthesis of catalysts 3a-c
In 150 mL two necked round-bottomed flask, the N-protected
thiazolidine 1a or 1b (15 mmol), anhydrous dichloromethane
(30 mL) and N-methylmorpholine (1.62 mL, 15 mmol) were added
under argon atmosphere at 0 °C. The solution was stirred for
30 min. then ethyl chloroformate (1.43 mL, 15 mmol) was added.
After 30 min. the aminoalcohol (15 mmol) was added and the
mixture was stirred for 24 h at rt. Then, the mixture was diluted
in dichloromethane (20 mL) and washed with 1 M NaOH and aque-
ous solution of NaCl. The organic layer was dried over Na2SO4 and
evaporated. The residue was dissolved in ethyl acetate (60 mL) and
a solution of 4.5 M HCl in ethyl acetate (54 mL) was added
dropwise at 0 °C. The suspension was stirred for 15 min. and then
the solvent was evaporated. The residue was dissolved in
dichloromethane and evaporated again. This procedure was
4.3. General procedure for organocatalytic asymmetric direct
aldol addition
A solution of a catalyst 3 in dry cyclic ketone (0.5 mL) was stir-
red at the temperature indicated in the tables, for around 2 h.
Aldehyde (1 mmol) was then slowly added and after addition of
brine (0.5 mL) the resulting mixture was stirred for the indicated
time. After that, the reaction mixture was treated with saturated
aqueous ammonium chloride solution (10 mL) and the whole mix-
ture was extracted with dichloromethane (3 ꢀ 20 mL). The organic
layer was dried over Na2SO4, and the solvent was removed under
vacuum. The crude mixture was purified by column chromatogra-
phy on silica gel with hexanes/ethyl acetate (80:20) being the
eluant. The enantiomeric excess (ee) was determined by HPLC
analysis using Chiracel OD-H or OJ-H and Chiralpak AD-H or AS-
H columns and the diastereomeric ratio was determined by 1H
NMR analysis.
repeated three times. The residue was then dissolved in
a
solution of CH2Cl2 1:1 H2O, cold to 0 °C and neutralized with
K2CO3. The organic layer was separated and the aqueous layer
washed with CH2Cl2 (3 ꢀ 50 mL). The combined organic extracts
were dried over Na2SO4 and evaporated. The residue was purified
with column chromatography or recrystallization to furnish the
product.
4.3.1. (S)-2-((R)-Hydroxy(phenyl)methyl)cyclohexanone 6a
This compound was obtained in a maximum yield of 66% with
ee = 99% and dr = >20:1. The enantiomeric excess was determined
by HPLC on Chiralcel OD-H (hexanes/2-propanol 90:10); 221 nm;
flow rate 0.5 mL/min; tR(major) = 9.38 min (S, R), tR(minor) = 12.48
4.2.1. (R)-N-((S)-1-Hydroxy-4-(methylthio)-1,1-diphenylbutan-
2-yl)thiazolidine-4-carboxamide 3a
This was prepared as per our general procedure to afford pro-
duct 3a. Recrystallization from CH2Cl2 furnished a white solid.
min (R, S). [a] [a]
20 = +18 (c 1, CHCl3) {lit.5 25 = +19 (c 1, CHCl3)}.
D D
Yield: 80%. Mp 152–154 °C. [
a
]
20 = ꢁ57 (c 1, CH2Cl2). IR (FT-IR/
1H NMR (300 MHz, CDCl3, d) 7.30 (5H, m), 4.79 (1H, d, J = 8.8 Hz),
4.05 (1H, s), 2.63 (1H, m), 2.49 (1H, m), 2.34 (1H, m), 2.06 (1H,
m), 1.62 (4H, m), 1.28 (1H, m).
D
ATR, cmꢁ1): 1515, 1651, 3324. 1H NMR (300 MHz, CDCl3) d: 7.55
(m, 4H), 7.44 (d, 1H, J = 9.2 Hz), 7.23 (m, 6H), 4.98 (m, 1H), 4.73
(br s, 1H), 3.98 (d, 1H, J = 10 Hz), 3.78 (dd, 1H, J = 4.8 Hz,
J = 7.3 Hz), 3.51 (d, 1H, J = 10 Hz), 2.97 (dd, 1H, J = 4.9 Hz,
J = 10.9 Hz), 2.81 (dd, 1H, J = 7.3 Hz, J = 10.8 Hz), 2.58 (m, 2H),
2.33 (br s, 1H), 1.95 (s, 3H), 1.84 (m, 1H). 13C NMR (75.5 MHz,
CDCl3) d: 172.1, 146.2, 144.1, 128.8, 128.1, 127.7, 127.3, 124.9,
81.2, 65.9, 56.1, 53.6, 35.1, 31.1, 28.2, 15.3. HRMS calculated for
[C21H26N2O2S2+Na]+: 425.5626, obtained: 425.5620.
4.3.2. (S)-2-((R)-Hydroxy(p-tolyl)methyl)cyclohexanone 6b
This compound was obtained in a maximum yield of 25% with
ee >99% and dr = 98:2. The enantiomeric excess was determined
by HPLC with chiral stationary phase: tR(major) = 25.27 min (S, R),
tR(minor) = 23.45 min (R, S).
[a]
D
[a]
25 = +17 (c 0.2, CHCl3) {lit.14
D
24 = +12.9 (c 0.17, CHCl3)}. 1H NMR (300 MHz, CDCl3) d 7.18–
7.02 (4H, m), 4.67 (1H, d, J = 8.8 Hz), 2.58–2.46 (1H, m), 2.45–
2.34 (1H, m), 2.34–2.17 (4H, m), 2.07–1.93 (1H, m), 1.77–1.63
(1H, m), 1.63–1.35 (3H, m), 1.30–1.12 (1H, m).
4.2.2. (R)-N-((R)-1-Hydroxy-3-mercapto-1,1-diphenylpropan-2-
yl)thiazolidine-4-carboxamide 3b
This was prepared as per our general procedure to afford
product 3b. Recrystallization from EtOH furnished
a
white
4.3.3. (S)-2-((R)-Hydroxy(4-methoxyphenyl)methyl)cyclohex-
anone 6c
solid. Yield: 65%. Mp 128–131 °C. [
a]
D
20 = ꢁ151 (c 1, CH2Cl2).
IR (FT-IR/ATR, cmꢁ1): 1522, 1655, 2554, 3334. 1H NMR
(300 MHz, CDCl3) d: 7.71 (m, 5H), 7.25 (m, 6H), 5.29 (br s,
2H), 4.01 (m, 1H), 3.76 (s, 2H), 3.08 (br s, 1H), 2.80 (m, 3H),
2.39 (br s, 1H). 13C NMR (CDCl3, 75.5 MHz) d: 172.1, 145.2,
144.1, 129.1, 128.9, 127.9, 125.5, 81.1, 66.1, 57.5, 53.4, 38.2,
35.1. HRMS calculated for [C19H22N2O2S2+Na]+: 397.5094,
obtained: 397.5090.
This compound was obtained in a maximum yield of 15% with
ee = 98% and dr = 89:11. The enantiomeric excess was determined
by HPLC with chiral stationary phase: tR(major) = 33.85 min (S, R),
tR(minor) = 30.60 min (R, S).
[a]
D
[a]
25 = +25 (c 1, CHCl3) {lit.5
D
25 = +30.5 (c 1.7, CHCl3)}. 1H NMR (300 MHz, CDCl3) d 7.17
(2H, d, J = 8.7 Hz), 6.81 (2H, d, J = 8.5 Hz), 4.67 (1H, d, J = 9.0 Hz),
3.87 (1H, br s), 3.73 (3H, s), 2.60–2.21 (3H, m), 2.09–1.92 (1H,
m), 1.83–1.38 (4H, m), 1.30–1.09 (1H, m).
4.2.3. (R)-N-((S)-1-Hydroxy-1,1,3-triphenylpropan-2-yl)-2,2-
dimethylthiazolidine-4-carboxamide 3c
This was prepared as per our general procedure to afford pro-
duct 3c. The residue was concentrated in vacuum and purified by
column chromatography with silica gel 230–400 Mesh with a mix-
ture of hexanes/ethyl acetate (1:1) as eluent to furnish the product
4.3.4. (S)-2-((R)-(4-Chlorophenyl)(hydroxy)methyl)cyclohex-
anone 6d
This compound was obtained in a maximum yield of 84% with
ee = 99% and dr = 96:4. The enantiomeric excess was determined
by HPLC with chiral stationary phase: tR(major) = 32.63 min (S, R),
Please cite this article in press as: Rambo, R. S.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.04.010

6
R. S. Rambo et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
tR(minor) = 27.29 min (R, S). [
a
]
25 = +20 (c 1, CHCl3) {lit.5 [
a
]
25 = +23.4
D
4.3.10. (S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclopentanone
6j
This compound was obtained in a maximum yield of 97% with
ee = 90% and dr = 68:32. The enantiomeric excess was determined
by HPLC with chiral stationary phase: tR(major) = 37.53 min (S, R),
D
(c 1.3, CHCl3)}. 1H NMR (300 MHz, CDCl3) d 7.36–7.07 (4H, m), 4.66
(1H, d, J = 8.5 Hz), 4.04 (1H, br s), 2.58–2.17 (3H, m), 2.02–1.86
(1H, m), 1.73–1.33 (4H, m), 1.26–1.05 (1H, m).
4.3.5. (S)-2-((R)-(4-Bromophenyl)(hydroxy)methyl)cyclohexanone
6e
This compound was obtained in a maximum yield of 60% with
ee = 99% and dr = 98:2. The enantiomeric excess was determined
by HPLC with chiral stationary phase: tR(major) = 18.57 min (S, R),
tR(minor) = 36.09 min (R, S).
[
a
]
25 = ꢁ25 (c 0.5, CHCl3) {lit.14
D
[a]
25 = ꢁ30.6 (c 0.56, CHCl3)}. 1H NMR (300 MHz, CDCl3) (Mixture
D
of anti/syn: 68:32) d 8.28–8.13 (2H, m), 7.61–7.45 (2H, m), 5.41
(0.32H, s, CH of syn diastereomer), 4.86 (0.68H, d, J = 8.9 Hz, CH
of anti diastereomer), 3.27 (1H, br s), 2.60–2.30 (2H, m),
2.19–1.89 (3H, m), 1.88–1.64 (2H, m).
tR(minor) = 15.76 min (R, S).
[a]
25 = +24 (c 1, CHCl3) {lit.14
D
[a]
D
24 = +22.6 (c 0.7, CHCl3)}. 1H NMR (300 MHz, CDCl3) d 7.38
(2H, d, J = 8.4 Hz), 7.11 (2H, d, J = 8.5 Hz), 4.66 (1H, d, J = 8.6 Hz),
3.98 (1H, br s), 2.58–2.19 (3H, m), 2.05–1.88 (1H, m), 1.75–1.26
(4H, m), 1.26–1.07 (1H, m).
Acknowledgments
We are grateful to the CAPES, CNPq, INCT-CMN and FAPERGS for
financial support. CNPq is also acknowledged for PhD fellowship
for R.S.R. and T.L.S.; CNPq is also acknowledged for undergradua-
tion fellowship for C.G.J.
4.3.6. 4-((R)-Hydroxy((S)-2-oxocyclohexyl)methyl)benzonitrile
6f
This compound was obtained in a maximum yield of 96% with
ee = 98% and dr = 96:4. The enantiomeric excess was determined
by HPLC with chiral stationary phase: tR(major) = 34.97 min (S, R),
References
tR(minor) = 27.37 min (R, S).
[a]
25 = +19 (c 1, CHCl3) {lit.5,14
D
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Alberto, E. E.; Paixão, M. W.; Soares, L. A.; Schneider, P. H.; Braga, A. L.
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Paixão, M. W.; Schneider, P. H. J. Mol. Catal. A 2005, 229, 47.
7. Braga, A. L.; Appelt, H. R.; Silveira, C. C.; Wessjohann, L. A.; Schneider, P. H.
Tetrahedron 2002, 58, 10413.
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Pergamon: New York, 1997.
[a]
D
25 = +20.1 (c 1.4, CHCl3)]. 1H NMR (300 MHz, CDCl3) d 7.64
(2H, d, J = 8.3 Hz), 7.45 (2H, d, J = 8.0 Hz), 4.85 (1H, d, J = 8.3 Hz),
4.12 (1H, br s), 2.64–2.31 (3H, m), 2.14–2.06 (1H, m), 1.84–1.79
(1H, m), 1.70–1.50 (3H, m), 1.42–1.32 (1H, m).
4.3.7. (S)-2-((R)-Hydroxy(2-nitrophenyl)methyl)cyclohexanone
6g
This compound was obtained in a maximum yield of 97% with
ee >99% and dr = 98:2. The enantiomeric excess was determined
by HPLC with chiral stationary phase: tR(major) = 17.29 min (S, R),
tR(minor) = 18.94 min (R, S).
[a]
D
[a]
25 = +15 (c 1, CHCl3) {lit.14
D
24 = +19.8 (c 1.6, CHCl3)}. 1H NMR (300 MHz, CDCl3) d 7.85
(1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 7.0 Hz), 7.64 (1H, t, J = 7.3 Hz),
7.43 (1H, t, J = 7.1 Hz), 5.43 (m, 1H), 4.20 (1H, d, J = 4.4 Hz), 2.83–
2.68 (1H, m), 2.50–2.27 (2H, m), 2.16–2.02 (1H, m), 1.91–1.51
(5H, m).
4.3.8. (S)-2-((R)-Hydroxy(3-nitrophenyl)methyl)cyclohexanone
6h
This compound was obtained in a maximum yield of 95% with
ee = 98% and dr = 91:9. The enantiomeric excess was determined
by HPLC with chiral stationary phase: tR(major) = 41.25 min (S, R),
tR(minor) = 53.82 min (R, S).
[a]
D
[a]
25 = +26 (c 1, CHCl3) {lit.14
D
25 = +32.5 (c 1.35, CHCl3)}. 1H NMR (300 MHz, CDCl3) d 8.21
(1H, s), 8.14 (1H, d, J = 8.2 Hz), 7.68 (1H, d, J = 7.6 Hz), 7.42 (1H, t,
J = 7.8 Hz), 4.92 (1H, d, J = 8.5 Hz), 4.20 (1H, br s), 2.72–2.58 (1H,
m), 2.57–2.28 (1H, m), 2.20–2.00 (1H, m), 1.91–1.75 (1H, m),
1.75–1.47 (3H, m), 1.46–1.28 (1H, m).
4.3.9. (S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexanone
6i
This compound was obtained in a maximum yield of 90% with
ee = 98% and dr = 91:9. The enantiomeric excess was determined
by HPLC with chiral stationary phase: tR(major) = 31.55 min (S, R),
tR(minor) = 23.24 min (R, S).
[a]
D
[a]
20 = +10 (c 1, CHCl3) {lit.14
D
25 = +12.8 (c 1.85, CHCl3)}. 1H NMR (300 MHz, CDCl3) d 8.10
(2H, d, J = 8.4 Hz), 7.43 (2H, d, J = 8.8 Hz), 4.83 (1H, d, J = 8.2 Hz),
4.11 (1H, br s), 2.61–2.49 (1H, m), 2.40–2.24 (2H, m), 2.11–1.96
(1H, m), 1.83–1.64 (1H, m), 1.64–1.41 (3H, m), 1.38–1.23 (1H, m).
14. Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417.
Please cite this article in press as: Rambo, R. S.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.04.010