Solvent-free asymmetric aldol reaction organocatalyzed by (S)-proline-containing thiodipeptides under ball-milling conditions

Article abstract of DOI:10.1016/j.tet.2011.10.093

An efficient, solvent-free ball-milling protocol for the asymmetric aldol reaction between cyclohexanone and cyclopentanone with various aromatic aldehydes using a novel series of (S)-proline-containing dipeptides and thiodipeptides 1a-f as organocatalysts is reported. In general, (S)-proline-containing thiodipeptides proved to be better organocatalysts relative to their analogous amides. In particular, thiodipeptide (S,S)-1d catalyzed the stereoselective formation of the expected aldol products with excellent diastereo- and enantioselectivity (up to 98:2 anti/syn dr and up to 96% ee). This observation may be ascribed to the increased N-H acidity of the thioamide segment that leads to stronger H-bonding interaction with the aldehyde carbonyl at the transition state and thus higher stereoinduction. Furthermore, thiodipeptide 1f proved to be an efficient organocatalyst for the aldol reaction of acetone with isatin and isatin derivatives (ee 56-86%).

Full text of DOI:10.1016/j.tet.2011.10.093

Tetrahedron 68 (2012) 92e97
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Solvent-free asymmetric aldol reaction organocatalyzed by (S)-proline-containing
thiodipeptides under ball-milling conditions
*
ꢀ
ꢀ
ꢀ
Jose G. Hernandez, Víctor García-Lopez, Eusebio Juaristi
ꢀ
ꢀ
ꢀ
Departamento de Química, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Apartado Postal 14-740, 07000 Mexico D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2011
Received in revised form 10 October 2011
Accepted 25 October 2011
Available online 3 November 2011
An efficient, solvent-free ball-milling protocol for the asymmetric aldol reaction between cyclohexanone
and cyclopentanone with various aromatic aldehydes using a novel series of (S)-proline-containing di-
peptides and thiodipeptides 1aef as organocatalysts is reported. In general, (S)-proline-containing thi-
odipeptides proved to be better organocatalysts relative to their analogous amides. In particular,
thiodipeptide (S,S)-1d catalyzed the stereoselective formation of the expected aldol products with ex-
cellent diastereo- and enantioselectivity (up to 98:2 anti/syn dr and up to 96% ee). This observation may
be ascribed to the increased NeH acidity of the thioamide segment that leads to stronger H-bonding
interaction with the aldehyde carbonyl at the transition state and thus higher stereoinduction. Fur-
thermore, thiodipeptide 1f proved to be an efficient organocatalyst for the aldol reaction of acetone with
isatin and isatin derivatives (ee 56e86%).
Keywords:
Organocatalysis
Ball-milling
Asymmetric aldol reaction
Thiodipeptides
Green chemistry
Isatin derivatives
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
fullerenes,5d synthesis of nitrones,5e 1,3-dipolar cycloaddition,5f
Sonogashira coupling,5g the HornereWadswortheEmmons reac-
In the past decade, the success of (S)-proline and (S)-proline-
derivatives as catalysts has promoted organocatalysis into a major,
intensively active field in organic chemistry.1 Among the out-
standing attributes of organocatalytic processes is the fact that this
strategy avoids the use of metals, implying that organocatalysis
fulfills one of the guidelines of green chemistry, where the design of
safer, less potentially toxic chemical processes is a key concept.2 In
this context, a powerful approach to ‘Green Chemistry’ seeks to
avoid the use of solvents as a strategy to make the synthetic pro-
tocol ‘greener’. For example, in asymmetric aldol reactions the use
of solvents such as DMSO, DMF, NMP, toluene or CHCl3 tends to
become a thing of the past. Furthermore, the design of more
energy-efficient processes such as those involving microwave
heating, ultrasound irradiation or mechanochemical activation is
becoming more common in recent years.3 In particular, High Speed
Ball-Milling (HSBM) is a sustainable mechanochemical technique,
which is being increasingly used in synthetic organic chemistry to
promote several synthetically useful reactions, under solvent-free
conditions.4 Reported applications of HSBM include: Heck-type
cross-couplings,5a Knoevenagel condensation reactions,5b Bay-
liseHillman reactions,5c Michael additions,5b functionalization of
tion,5h synthesis of peptides,5iej and others.
Pioneers in the field of the organocatalytic aldol reaction under
HSBM conditions, Bolm and co-workers reported the asymmetric
aldol reaction under solvent-free conditions and catalyzed by (S)-
proline (10 mol %) in a ball mill, employing a 1.1:1 ketone/aldehyde
ratio to afford principally the anti-aldol products in high yields and
with up to 99% ee.6 In this study, Bolm and co-workers demon-
strated that the efficiency of the process using High Speed Ball-
Milling (HSBM) was superior relative to traditional magnetic stir-
ring: reaction times were shorter, and chemical yields and stereo-
7
selectivities were higher.6 In this regard, Najera and co-workers
ꢀ
have reported the use of (Sa)-binam-L-prolinamides (10 mol %) as
organocatalysts in solvent-free aldol reactions between cyclohex-
anone and p-nitrobenzaldehyde (8:1 ratio) using a planetary ball
mill. The anti-aldol adduct was obtained in high yield and with
good diastereo- and enantioselectivity (up to 69:31 dr, up to 88%
ee).7 Recently, as part of our continuing interest in synthetic ap-
plications of HSBM,5i,8a,b we carried out the asymmetric aldol re-
action between representative ketones and various aromatic
aldehydes under solvent-free conditions in a ball mill, using es-
sentially stoichiometric amounts of the starting ketone and alde-
hyde (1.1:1). The reaction was catalyzed by the methyl ester of
(S)-proline-(S)-phenylalanine, (S,S)-1a (7 mol %) and proceeded
efficiently to afford mainly the anti diastereomeric aldol product
in high yield and with good enantioselectivity (up to 91:9 dr, and
* Corresponding author. Tel.: þ52 55 5747 3722; fax: þ52 55 5747 3389; e-mail
addresses: juaristi@relaq.mx, ejuarist@cinvestav.mx (E. Juaristi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.093

ꢀ
J.G. Hernandez et al. / Tetrahedron 68 (2012) 92e97
93
up to 95% ee) (Fig. 1).8a We suggested that dipeptide 1a is a more
efficient organocatalyst in the solvent-free asymmetric aldol re-
action relative to the same reaction in solution, probably because
(5e20 mol %) in aldol reactions between representative ketones
and various aromatic aldehydes in high yields (up to 97%), and with
high diastereo- and enantioselectivity (up to 95:5 dr and 98% ee).10
ꢀ
under solvent-free conditions non-covalent
pe
p
interactions be-
Furthermore, Najera and co-workers compared the organocatalytic
tween the aromatic rings of the catalyst and the substrate are
maximized, leading to a tighter transition state and thus higher
stereoinduction.
activity of (S)-prolinamides and (S)-prolinethioamides in the aldol
reaction of aliphatic ketones (2 equiv) with aromatic aldehydes,
demonstrating that (S)-prolinethioamides are superior catalysts
relative to (S)-prolinamides, affording the anti-aldol adducts in
higher yields and with excellent diastereo- and enantioselectivities
(up to 98:2 dr, and up to 98% ee).11 More recently, Li and co-workers
confirmed the superior catalytic activity of (S)-prolinethioamides
relative to the analogous (S)-prolinamides in the direct asymmetric
aldol reaction of acetone (5 equiv) with various aromatic aldehydes.
In aqueous media, the reaction catalyzed by (S)-proline-containing
thioamides (0.1e0.2 mol %) in the presence of PhCO2H (2 mol %)
afforded the aldol adducts in excellent enantioselectivities and
yields (up to 99% ee in 98% yield).12a Finally, in 2009 Li and co-
workers prepared several organocatalysts derived from (S)-proline,
such as dipeptide (S)-Pro-(S)-ValeCO2Me, and its thio analog (S)-
Pro(C]S)-(S)-ValeCO2Me.
X
X
X
N
H
N
H
N
H
HN
HN
HN
NH
OMe
OMe
1b
OMe
O
O
O
1a
1c
X = O (S,S)-
X = O (S,S)-
X = S (S,S)-
X = O (S,S)-
1d
1e
1f
X = S (S,S)-
X = S (S,S)-
Fig. 1. Structure of (S,S)-dipeptides 1aec and (S,S)-thiodipeptides 1def examined as
potential organocatalysts under ball-milling conditions in this study.
In more recent work, we reported the asymmetric aldol re-
action between ketones and various aromatic aldehydes under
solvent-free conditions in a ball mill, with catalysis by (S)-proline-
containing dipeptides (S,S)-1b and (S,S)-1c (Fig. 1), which were
obtained by condensation with of (S)-proline with (S)-phenyl-
glycine or (S)-tryptophan, respectively. It was observed that in the
presence of an equimolar amount of water and a catalytic amount
of benzoic acid, dipeptide (S,S)-proline-tryptophaneCO2Me 1c
(3 mol %) is a particularly efficient catalyst. This result is in
agreement with expectation that dipeptides of proline and a sec-
ond hydrophobic residue are efficient catalysts in aldol reactions
owing apparently to the formation of a hydrophobic core that
maximizes the influence of non-bonding interactions in the ster-
eoinducing transition state. We also suggested that molecules of
water may be involved in the formation of hydrogen bonds with
the carbonyl amide group in dipeptide (S,S)-1c. Such interaction
would enhance the acidity of the NeH amide bond and provide
stronger hydrogen bonding with the aldehyde substrate, fixing its
orientation in the transition state and promoting higher stereo-
selectivity in the aldol process.8b
The evaluation of both catalysts in the enantioselective direct
aldol reaction between acetone and 4-nitrobenzaldehyde in DMSO
solution and in the presence of 10 mol % of benzoic acid as additive
revealed that the (S,S)-thiodipeptide afforded the aldol product in
better yield and higher enantioselectivity (72% yield, 85% ee) rela-
tive to the same reaction using the (S,S)-dipeptide (59% yield, 35%
ee).12b
Nevertheless, no evaluation of (S,S)-proline-containing thio-
dipeptides as potential organocatalysts in aldol reactions under
solvent-free reaction conditions has been reported in the literature.
For this reason we decided to synthesize the three novel (S,S)-
prolinethiodipeptides 1def (Fig. 1), and compare their organo-
catalytic activity in the asymmetric aldol reaction with that
exhibited by the analogous 1aec.
2. Results and discussion
(S)-Proline-containing dipeptides and thiodipeptides (S,S)-1aef
were synthesized by condensation of Cbz- or Boc-N-protected (S)-
proline with (S)-phenylalanine, (S)-phenylglycine, or (S)-trypto-
phan methyl ester hydrochloride. The dipeptides 1aec were ob-
tained by deprotection of Cbz-N-protected dipeptides with
hydrogen and palladium on carbon. On the other hand, Boc-N-
protected dipeptides were treated with Lawesson’s reagent, fol-
lowed by deprotection of the amine function with trifluoroacetic
acid to afford the desired thiodipeptides 1def (Scheme 1).
One way to increase the strength of the proposed H-bonding
interaction would be through the replacement of the amide group
with the thioamide functionality in proline derivatives, as conse-
quence of the higher acidity of the NeH function present in a thi-
oamide relative to the NeH group present in the analogous amide
segment.9 In this regard, Gryko and co-workers recently reported
the use of
L-proline-containing thioamides as organocatalysts
Scheme 1. Synthesis of organocatalysts (S,S)-1aef.

ꢀ
J.G. Hernandez et al. / Tetrahedron 68 (2012) 92e97
94
Initially, we examined the aldol reaction between cyclohexa-
all cases the diastereoselectivity in favor of the anti-diastereomer
was significantly improved affording the major anti-product in
>98:2 dr (entries 4e9 in Table 2). Nevertheless, the use of water or
benzoic acid did not improve the ee of the major (2S,10R)-enan-
tiomer. By the same token, using 7 mol % of catalyst 1d, 1.0 equiv of
water, and 5 mol % of benzoic acid the diastereoselectivity of the
process was improved (99:1 anti/syn), but the anti-aldol product
was obtained in only 85% ee (entry 10 in Table 2).
none and 3-nitrobenzaldehyde in the presence of organocatalysts
1aef. The reaction was carried out at ꢀ20 ꢁC in a ball mill at
2760 rpm (entries 1e6 in Table 1). After 4 h of milling, all six cat-
alysts 1aef afforded the aldol product in good yield, high diastereo-
and enantioselectivity. Nevertheless, (S,S)-thiodipeptides 1def
proved to be better organocatalysts in the asymmetric aldol re-
action of interest (compare entries 1e3 with 4e6 in Table 1). In
particular, with thiodipeptide (S,S)-1d as catalyst the aldol adduct
was obtained with up to 93:7 anti/syn dr and 96% ee in favor of the
(2S,10R)-enantiomer (entry 4 in Table 1). The absolute configuration
of the products was assigned by comparison with literature
data.6,11a,13
Following thorough evaluation of the essential reaction pa-
rameters (Table 2), we proceeded to employ (S,S)-1d, as organo-
catalyst in the direct asymmetric aldol reaction between
cyclohexanone 2a and cyclopentanone 2b with several benzalde-
hyde derivatives containing different substituents 3aek (Table 3).
The nitro, chloro, bromo, and cyano substituents were chosen as
electron-withdrawing groups, and the methoxy substituent as
a representative electron-donating group. Reactions of cyclohexa-
none with electron-deficient aromatic aldehydes provided the de-
sired anti-aldol products in good isolated yields (70e89%) with
high diastereo- (92:8 to >98:2 anti/syn) and enantioselectivities
(82e96% ee) (entries 1e9 in Table 3). When catalyst (S,S)-1d was
used in the aldol condensation of cyclohexanone with non-
activated aldehydes, such as benzaldehyde and p-anisaldehyde,
even after prolonged reaction times the aldol adducts 4jek were
obtained in only moderate yields, with good diastereo- (>90:10
anti/syn), and moderate enantioselectivities (50e86% ee) (entries
10 and 11 in Table 3). Finally, the reaction of cyclopentanone with 4-
nitrobenzaldehyde generated a 70:30 mixture of anti- and syn-di-
astereoisomers of product 4l in 76% yield. The anti-product pre-
sented 66% ee (entry 12 in Table 3). It is noteworthy that aldol
product 4l was obtained with anti-diastereoselectivity using thio-
dipeptide (S,S)-1d (70:30 anti/syn), since literature precedent
shows a slight preference for the syn-isomer in going from cyclo-
hexanone to cyclopentanone.14
Table 1
Relative catalytic activity of dipeptides (S,S)-1aec and thiodipeptides (S,S)-1def in
the asymmetric aldol reaction of cyclohexanone with 3-nitrobenzaldehyde under
ball-milling conditionsa
Entry
Cat. (mol %)
Yieldb (%)
drc (anti/syn)
eed (%)
1
2
3
4
5
6
1a (7)
1b (7)
1c (7)
1d (7)
1e (7)
1f (7)
94
80
90
81
68
75
88:12
89:11
93:7
>93:7
90:10
96:4
85
80
88
96
91
92
a
Reaction conditions: ketone 2a (0.22 mmol), aldehyde 3b (0.20 mmol), ꢀ20 ꢁC,
4.0 h.
b
c
Isolated yield.
Determined by 1H NMR of the crude product.
Determined by chiral HPLC (anti-isomer).
d
To account for the formation of the predominant anti-products,
we propose a transition state similar to those that have been sug-
gested where catalysis by dipeptides15 and prolinamides is operative
(Fig. 2).16 The pyrrolidine functionality in (S,S)-1d activates the ke-
tone through the formation of a chiral enamine intermediate, while
the aldehyde is activated through the formation of a strong hydrogen
bond involving the thioamide NeH hydrogen atom.9e12 In addition,
it appears that under solvent-free reactions conditions, non-covalent
We also examined the effect of the amount of catalyst (S,S)-1d.
This analysis revealed that the best results are obtained when using
7 mol % of catalyst (entries 1e3 in Table 2). On the other hand, in
our previous work we had shown that the use of water and acidic
additives could be beneficial for the stereoinduction of the proc-
ess.8b With this precedent, we carried out the reaction between
cyclohexanone and 3-nitrobenzaldehyde at ꢀ20 ꢁC, catalyzed by
7 mol % of (S,S)-1d, and in the presence of water and benzoic acid. In
pep interactions between aromatic rings of the catalyst and the al-
dehydes are enhanced, and thus the hydrophobic organocatalyst and
the aromatic region of the aldehyde may engage in a more rigid
transition state that induces higher stereoselectivity.8a,b,17
Table 2
Reaction parameters evaluated in the direct asymmetric aldol reaction of 3-
nitrobenzaldehyde with cyclohexanone catalyzed by organocatalyst 1da
The majority of the reports in the field of organocatalytic
asymmetric aldol reactions involve the use of aldehydes as accep-
tors. By contrast, studies where ketones act as electrophiles have
been less explored, despite the fact that this reaction may provide
efficient access to chiral tertiary alcohols. In particular, the use of
isatin as an electrophile is very attractive because the reaction af-
fords chiral hydroxy oxyindole derivatives, which are an important
structural motif in numerous natural products and in biologically
active molecules.18 In 2005, Tomasini and co-workers reported the
asymmetric aldol reaction between isatin and acetone, catalyzed by
O
O
O
OH
NO2
1d
NO2
Cat.
+
H
syn isomer
+
Ball-milling
2760 rpm
anti isomer
4b
2a
3b
Entry
Cat. 1d
(mol %)
H2O
(equiv)
PhCO2H
(mol %)
Yieldb
(%)
dr
eed
(%)
(anti/syn)c
1
2
3
4
5
6
7
8
9
(10)
(7)
(3)
(7)
(7)
(7)
(7)
(7)
(7)
(7)
d
d
d
1
3
5
d
d
d
1
d
d
d
d
d
d
5
10
15
5
85
81
65
72
76
85
78
83
85
78
>98:2
>93:7
90:10
>95:5
94:6
>95:5
>98:2
>98:2
>98:2
99:1
90
96
87
90
89
87
90
91
87
85
a,a- and a,b-proline-containing dipeptides (10 mol %). The 3-(2-
oxopropyl)-3-hydroxyindolin-2-one 6a was obtained in good to
excellent yields and with good enantioinduction (ee 20e73%).19 In
view of this precedent, we decided to compare the organocatalytic
activity of (S,S)-dipeptides 1aec and thiodipeptides (S,S)-1d and
(S,S)-1f in the challenging aldol reaction between isatin and ace-
tone, under traditional solution conditions vis-a-vis solvent-free
conditions using High Speed Ball-Milling (HSBM) (Table 4).
The results reveal that reactions employing HSBM afford the
desired product 6a in moderate yield, using 3 equiv of acetone.
Furthermore, the enantiomeric excesses in aldol product 6a were
10
a
Reaction conditions: ketone 2a (0.22 mmol), aldehyde 3b (0.20 mmol), ꢀ20 ꢁC,
4.0 h.
b
c
Isolated yield.
Determined by 1H NMR of the crude product.
Determined by chiral HPLC (anti-isomer).
d

ꢀ
J.G. Hernandez et al. / Tetrahedron 68 (2012) 92e97
95
O
MeO
S
Table 3
N
H
Scope of the direct asymmetric aldol reaction of cyclic ketones with various alde-
hydes catalyzed by (S,S)-1d under ball-milling conditionsa
O
O
OH
O
N
NO2
O
1d
7 mol% (S,S)-
+
H
+
R
syn isomer
R
H
Ball-milling
2760 rpm
anti isomer
2
3
4
Fig. 2. Suggested transition state model for the aldol reaction catalyzed by (S,S)-1d
with 3-nitrobenzaldehyde.
Entry
1
Product
Yieldb (%)
89
dr (anti/syn)c
eed (%)
91
O
OH
Table 4
98:2
Organocatalytic asymmetric aldol reaction of isatin with acetone under traditional
solution vis-a-vis solvent-free conditions (HSBM) catalyzed by (S,S)-dipeptides 1aec
and (S,S)-thiodipeptides 1d and 1f
NO2
NO2
4a
O
OH
O
O
HO
2
3
86
80
92:8
96
93
O
Cat. 10 mol%
O
+
4b
O
N
H
N
H
O
OH
NO2
5a
2c
6a
>98:2
Entry
Cat.
Media
Yieldc (%)
eed (%)
4c
1
2
3
4
5
6
7
8
1a
1b
1c
1a
1b
1c
1d
1f
Solutiona
62
47
72
33
52
60
30
54
39
31
24
38
35
50
48
56
Solutiona
O
OH
Solutiona
4
5
74
70
>97:3
>93:7
89
87
Ball-millingb
Ball-millingb
Ball-millingb
Ball-millingb
Ball-millingb
4d
Cl
O
OH
Cl
a
Reaction conditions in solution: isatin 5a (0.20 mmol), acetone 2c (90 equiv;
18 mmol), ꢀ20 ꢁC, 4.0 h, magnetic stirring.
4e
b
Solvent-free condition using HSBM: isatin 5a (0.20 mmol), acetone 2c (3 equiv;
O
OH
Cl
0.6 mmol), ꢀ20 ꢁC, 4.0 h, 2760 rpm.
c
6
7
78
82
98:2
97:3
90
88
Isolated yield.
Determined by chiral HPLC.
d
4f
O
OH
superior when using HSBM, relative to the reaction under tradi-
tional magnetic stirring in solution. In particular, dipeptide (S,S)-1c
afforded the expected (S)-3-hydroxyindolinone 6a in 50% ee, to be
compared with 24% ee in solution (entries 3 and 6 in Table 4, re-
spectively). On the other hand, by using (S,S)-thiodipeptides 1d and
1f instead of dipeptides 1a and 1c, the enantioselectivity of 6a
reached 48 and 56%, respectively (cf. entries 4, and 6e8 in Table 4).
The efficiency of thiodipeptide (S,S)-1f in the direct asymmetric
aldol reaction between acetone 2c with isatin derivatives 5aee was
also examined (Scheme 2).
4g
Br
O
OH
Br
8
9
77
80
97:3
82
87
4h
O
OH
>97:3
4i
CN
The use of N-methyl- and N-benzyl-protected isatins 5b, c led to
an improvement in the enantioselectivity of the aldol product,
affording the (S)-1-alkyl-3-hydroxyindolinones 6b and 6c in 62 and
65% ee, respectively. Most interestingly, it was found that the use of
isatins containing electron-withdrawing groups on the aromatic ring
tended to generate the aldol product with higher enantioselectivities.
In particular product 6e was obtained with 86% ee (Scheme 2).
O
OH
10
11
63e
51e
92:8
86
50
4j
O
OH
90:10
4k
OMe
NO2
3. Conclusion
OH
O
In summary, (S,S)-dipeptides and (S,S)-thiodipeptides 1aef are
excellent catalysts for the asymmetric direct aldol intermolecular
reaction under solvent-free conditions using the High Speed Ball-
Milling (HSBM) technique. In general, the organocatalytic activity
of thiodipeptides 1def is superior relative to that exhibited by di-
peptides 1aec. This may be due to the increased NH acidity for
thioamides relative to amides. In particular, thiodipeptide (S,S)-1d,
which was readily prepared from commercially available and in-
expensive (S)-proline and (S)-phenylalanine proved to be the most
efficient catalyst, affording the anti-aldol products in good yields
12
76
70:30
66
4l
a
Reaction conditions: ketone 2a, b (0.22 mmol), aldehyde 3aek (0.20 mmol),
ꢀ20 ꢁC, 6.0 h.
b
c
Isolated yield.
Determined by 1H NMR of the crude product.
Determined by chiral HPLC (anti-isomer).
Milling 8.0 h.
d
e

ꢀ
J.G. Hernandez et al. / Tetrahedron 68 (2012) 92e97
96
O
added a solution of isobutyl chloroformate (1.75 mL,13.41 mmol) in
5 mL of CH2Cl2 dropwise over 20 min. The resulting solution was
stirred at ꢀ10 ꢁC for 20 min before a solution of the corresponding
O
HO
O
R1
R1
Cat. (S,S)-1f
+
O
O
O
a
-amino ester hydrochlorides (2.6 g, 12.05 mmol for L-phenylala-
Ball-milling
N
R
N
R
nine) and NMM (1.60 mL, 14.55 mmol) in dry CH2Cl2 was added
dropwise over 20 min. After 2 h at ꢀ10 ꢁC the mixture was allowed
to warm to room temperature and further stirred overnight. The
mixture was concentrated and extracted with EtOAc. The organic
phase was washed with 1 N HCl, satd NaHCO3 and brine, dried over
anhydrous Na2SO4, and concentrated. The residue was purified by
column chromatography using CH2Cl2/MeOH (95:5 v/v) as eluent
5a-e
2c
6a-e
O
O
O
HO
HO
HO
O
O
N
Bn
N
N
to afford the respective N(Cbz)e
L-Pro-
L-aaeCO2Me dipeptide. To
H
each of the solution of N(Cbz)e
L
-Pro-L-aaeCO2Me dipeptide
6a
6b
6c
(500 mg) in 20 mL AcOEt/MeOH (4:1),10% Pd/C (50 mg) was added,
followed by stirring for 5 h under hydrogen balloon. The reaction
mixture was filtered and washed with methanol, and the filtrate
was concentrated.
The crude product was purified by column chromatography to
afford the desired dipeptide NHeL-Pro-L-aaeCO2Me 1aec.
yield 54%
ee 56%
yield 68%
ee 62%
yield 60%
ee 65%
O
O
O
HO
HO
O2N
Br
O
N
H
N
H
4.2.1. (S,S)-Proline-phenylalanine methyl ester, 1a. Rf¼0.35 [silica
22
gel, DCM/MeOH 95:5], [
a
]
D
ꢀ4.7 (c 1.0, CH3Cl), (FTIR/ATR, cmꢀ1
)
6d
yield 65%
ee 69%
6e
nmax 3324, 2951, 1740, 1667. 1H NMR (500 MHz, CDCl3)
d 8.06 (1H, br
yield 61%
ee 86%
d, J¼8.3 Hz), 7.29e7.18 (3H, m), 7.13e7.08 (2H, m), 4.83 (1H, m), 3.71
(3H, s), 3.67 (1H, m), 3.16 (1H, dd, J¼5.6, 13.9 Hz), 3.02 (1H, dd,
J¼7.3, 13.9 Hz), 2.91 (1H, m), 2.72 (1H, m), 2.24 (1H, br s), 2.03 (1H,
m), 1.72 (1H, m), 1.64e1.45 (2H, m) ppm. 13C NMR (125 MHz, CDCl3)
Scheme 2. 3-Hydroxyindolinones obtained under solvent-free conditions (HSBM)
catalyzed by thiodipeptide (S,S)-1f. All reactions were performed using 5aee
(0.20 mmol), 2c (0.60 mmol), 1f (10 mol %), ꢀ20 ꢁC, 4.0 h, 2760 rpm. Enantiomeric
excesses were determined by chiral-stationary-phase HPLC (Ref. 20).
d
174.9, 172.0, 136.1, 129.2, 128.3, 126.9, 60.2, 52.4, 52.2, 47.1, 38.0,
30.6, 26.0 ppm. HR-ESI-TOF: calculated for C15H21N2O3 [MþH]þ:
277.1546; found: 277.1551 (1.5 ppm error).
with high diastereo- and enantioselectivity. It is worth mentioning
that all aldol products were obtained with higher diaster-
eoselectivity and in most cases with higher enantioselectivity by
the use of 7 mol % of thiodipeptide (S,S)-1d, relative to the same
reaction employing 7 mol % of dipeptide (S,S)-1a.
On the other hand, the aldol reaction using isatin as carbonylic
substrate proceeded in higher yield with better enantioselectivity
under solvent-free conditions in a ball mill, relative to the same
reaction in solution with traditional magnetic stirring. (S,S)-Thio-
dipeptide 1f proved to be the best organocatalyst in the aldol re-
action between isatin derivatives and acetone under HSBM
conditions.
4.2.2. (S,S)-Proline-phenylglycine methyl ester, 1b. Rf¼0.32 [silica
22
gel, DCM/MeOH 95:5], [
a]
ꢀ13.0 (c 1.0, CH3Cl), (FTIR/ATR, cmꢀ1
)
D
nmax 3327, 2952,1742,1661. 1H NMR (500 MHz, CDCl3)
d 8.45 (1H, br
d, J¼5.5 Hz), 7.37e7.27 (5H, m), 5.56 (1H, d, J¼8.0 Hz), 3.75 (1H, m),
3.70 (3H, s), 2.95 (2H, m), 2.16 (1H, br s), 2.09 (1H, m), 2.02e1.84
(1H, m), 1.80e1.64 (2H, m) ppm. 13C NMR (125 MHz, CDCl3)
d 174.8,
171.5, 137.0, 129.0, 128.5, 127.3, 60.7, 56.1, 52.6, 47.4, 30.7, 26.2 ppm.
HR-ESI-TOF: calculated for C14H19N2O3 [MþH]þ: 263.1390; found:
263.1393 (1.1 ppm error).
4.2.3. (S,S)-Proline-tryptophan methyl ester, 1c. Rf¼0.30 [silica gel,
22
DCM/MeOH 95:5], [
a]
þ2.2 (c 2.1, CH3Cl), (FTIR/ATR, cmꢀ1
) nmax
d 8.63 (1H, br s),
D
3297, 2951, 1737, 1650. 1H NMR (500 MHz, CDCl3)
4. Experimental section
8.11 (1H, d, J¼8.5 Hz), 7.54 (1H, d, J¼7.5 Hz), 7.32 (1H, d, J¼8.0 Hz),
7.15 (1H, dt, J¼7.5, 1.3 Hz), 7.08 (1H, dt, J¼7.5, 1.0 Hz), 6.94 (1H, d,
J¼2.4 Hz), 4.94e4.87 (1H, m), 3.68 (3H, s), 3.67e3.63 (1H, m), 3.30
(2H, d, J¼6.0 Hz), 2.86e2.80 (1H, m), 2.64e2.58 (1H, m), 2.12e1.98
(2H, m), 1.77e1.68 (1H, m), 1.60e1.42 (2H, m) ppm. 13C NMR
4.1. General remarks
1H and 13C NMR spectra were recorded on a 500 MHz spec-
trometer. Chemical shift (d) are given in parts per million downfield
from tetramethylsilane as an internal reference, coupling constants
J are given in hertz. Molecular weights were determined by means
of High-resolution mass spectrometry (HRMS). Infrared spectra (IR)
were reported in reciprocal centimeters. Enantiomeric excess was
measured by chiral HPLC at room temperature using a Waters 600 E
equipment fitted with an UVevisible Waters 2487 detector at 220,
254, 258 or 260 nm with Chiralpak AD-H, Chiralcel OD-H and OJ
columns. Reactions carried out under ball-milling conditions were
performed in a digital Amalgamator, fitted with a reactor (cylinder,
25 mm long and with a diameter 10 mm) containing one stainless
steel ball of 5 mm diameter.
(125 MHz, CDCl3)
d 175.4, 172.7, 136.2, 127.7, 122.8, 122.1, 119.5,
118.6, 111.3, 110.1, 60.4, 52.6, 52.4, 47.2, 30.7, 27.9, 26.2 ppm. HR-ESI-
TOF: calculated for C17H22N3O3 [MþH]þ: 316.1655; found: 316.1659
(1.0 ppm error).
4.3. Preparation of methyl ester (S)-proline-containing
thiodipeptides 1def
To a solution of N-BoceL-proline (2.0 g, 9.30 mmol) and NMM
(1.13 mL, 10.3 mmol) in dry THF (60 mL) under nitrogen at ꢀ10 ꢁC
was added
a solution of isobutyl chloroformate (1.36 mL,
10.4 mmol) in 5 mL of CH2Cl2 dropwise over 20 min. The resulting
4.2. Preparation of methyl ester (S)-proline-containing
dipeptides 1aec
solution was stirred at ꢀ10 ꢁC for 20 min before a solution of the
corresponding a-amino ester hydrochlorides (2.01 g, 9.31 mmol for
L
-phenylalanine) and NMM (1.24 mL, 11.27 mmol) in dry CH2Cl2
To a solution of N-Cbze
L
-proline (3.0 g, 12.03 mmol) and NMM
was added dropwise over 20 min. After 2 h at ꢀ10 ꢁC the mixture
(1.45 mL, 13.19 mmol) in dry THF under nitrogen at ꢀ10 ꢁC was
was allowed to warm to room temperature and further stirred

ꢀ
J.G. Hernandez et al. / Tetrahedron 68 (2012) 92e97
97
overnight. The mixture was concentrated and extracted with
EtOAc. The organic phase was washed with satd NaHCO3 and brine,
dried over anhydrous Na2SO4, and concentrated. The residue was
purified by column chromatography using hexane/EtOAc (5:1 v/v)
chromatography (silica gel, hexane/EtOAc: 10:1 to 3:1) to afford the
expected syn/anti-aldol mixture.
Acknowledgements
as eluent to afford the respective N(Boc)e
L-Pro-L-aaeCO2Me di-
peptide. A mixture of each N(Boc)e -Pro- -aaeCO2Me dipeptide
L
L
ꢀ
The authors are indebted to Conacyt, Mexico for financial sup-
(1.1 g, 2.92 mmol for N(Boc)ePro-PheCO2Me) and Lawesson’s re-
agent (1.37 mg, 3.4 mmol) in dry THF (50 mL) was stirred for 2 h at
room temperature and then refluxed for 0.5 h under nitrogen at-
mosphere. The reaction mixture was concentrated under reduced
pressure and was purified by column chromatography using hex-
ane/EtOAc (10:1 to 2:1 v/v) to afford the respective N(Boc)-thio-
dipeptide. Each N(Boc)-thiodipeptide (540 mg, 1.37 mmol for
N(Boc)ePro-(C]S)-PheCO2Me) was dissolved in dry CH2Cl2
(2.8 mL) and then TFA (1.4 mL) and i-Pr3SiH (0.5 mL) was added.
After 2 h the solvent was removed and the residue was dissolved
with CH2Cl2 and washed with satd NaHCO3. The organic fraction
was separated, dried over anhydrous Na2SO4, and concentrated to
afford the desired NH-thiodipeptide 1def.
ꢀ
port via grant 60366-Q. J.G.H. thanks Conacyt, Mexico for a doctoral
fellowship (No. 22211).
Supplementary data
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2011.10.093.
References and notes
1. For recent discussions on proline and proline-derived organocatalysts, see:;
Yamamoto, H., List, B., Eds. Special Cluster. Synlett 2011, 461e512.
2. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford Uni-
versity Press: New York, NY, 1998, pp 30e31.
3. See, for example; Bruckmann, A.; Krebs, A.; Bolm, C. Green Chem. 2008, 10,
1131e1141.
4.3.1. (S,S)-Thio-proline-phenylalanine methyl ester, 1d. Rf¼0.24
4. (a) Stolle, A.; Szuppa, T.; Leonhardt, S. E. S.; Ondruschka, B. Chem. Soc. Rev. 2011,
40, 2317e2329; (b) James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.;
22
[silica gel, DCM/MeOH 30:1], [
a
]
þ61 (c 1.0, CH2Cl2), (FTIR/ATR,
D
cmꢀ1
CDCl3)
)
nmax 3174, 2948, 2868, 1740, 1505. 1H NMR (500 MHz,
10.25 (1H, br), 7.30e7.20 (3H, m), 7.11e7.06 (2H, m), 5.36
ꢁꢁ ꢀ
Friscic, T.; Grepioni, F.; Harris, K. D. M.; Hyett, G.; Jones, W.; Krebs, A.; Mack, J.;
Maini, L.; Orpen, A. G.; Parkin, I. P.; Shearouse, W. C.; Steed, J. W.; Waddell, D. C.
Chem. Soc. Rev. 2012, , doi:10.1039/C1CS15171A Advance article.
d
(1H, br), 4.13 (1H, dd, J¼5.3, 9.3 Hz), 3.74 (3H, s), 3.38 (1H, dd,
J¼5.8, 13.9 Hz), 3.18 (1H, dd, J¼5.7, 13.7 Hz), 2.95 (1H, m), 2.70 (1H,
m), 2.30 (1H, m), 2.05 (1H, br), 1.88 (1H, m), 1.61 (1H, m), 1.44 (1H,
5. (a) Tullberg, E.; Peters, D.; Frejd, T. J. Organomet. Chem. 2004, 689, 3778e3781;
(b) Kaupp, G.; Naimi-Jamal, M. R.; Schmeyers, J. Tetrahedron 2003, 59,
3753e3760; (c) Mack, J.; Shumba, M. Green Chem. 2007, 9, 328e330; (d) Ko-
matsu, K. Top. Curr. Chem. 2005, 254, 185e206; (e) Colacino, E.; Nun, P.; Cola-
cino, F.-M.; Martinez, J.; Lamaty, F. Tetrahedron 2008, 64, 5569e5576; (f)
Thorwirth, R.; Stolle, A.; Ondruschka, B.; Wild, A.; Schubert, U. S. Chem. Com-
mun. 2011, 4370e4372; (g) Thorwirth, R.; Stolle, A.; Ondruschka, B. Green Chem.
2010, 12, 985e991; (h) Shearouse, W. C.; Korte, C. M.; Mack, J. Green Chem. 2011,
m) ppm. 13C NMR (125 MHz, CDCl3)
d 205.7, 170.9, 135.5, 129.0,
128.3, 127.0, 67.8, 57.1, 52.3, 47.1, 36.5, 34.3, 25.7 ppm. HR-ESI-TOF:
calculated for C15H21N2O2S [MþH]þ: 293.1318; found: 293.1323
(1.6 ppm error).
ꢀ
13, 598e601; (i) Hernandez, J. G.; Juaristi, E. J. Org. Chem. 2010, 75, 7107e7111;
(j) Lamaty, F.; Martinez, J.; Nun, P.; Declerck, V. Angew. Chem., Int. Ed. 2009, 48,
4.3.2. (S,S)-Thio-proline-phenylglycine methyl ester, 1e. Rf¼0.16
9318e9321.
22
6. Rodríguez, B.; Bruckmann, A.; Bolm, C. Chem.dEur. J. 2007, 13, 4710e4722.
7. (a) Guillena, G.; Hita, M. C.; Najera, C.; Viozquez, S. F. Tetrahedron: Asymmetry
[silica gel, DCM/MeOH 30:1], [
a
]
þ93.9 (c 1.0, CH2Cl2), (FTIR/
D
ꢀ
ꢀ
ATR, cmꢀ1
)
nmax 3178, 2948, 2868, 1740, 1497. 1H NMR (500 MHz,
ꢀ
ꢀ
2007, 18, 2300e2304; (b) Guillena, G.; Hita, M. C.; Najera, C.; Viozquez, S. F. J.
Org. Chem. 2008, 73, 5933e5943.
CDCl3) 10.73 (1H, br), 7.42e7.30 (5H, m), 6.07 (1H, s), 4.23 (1H,
d
ꢀ
8. (a) Hernandez, J. G.; Juaristi, E. J. Org. Chem. 2011, 76, 1464e1467; (b)
dd, J¼5.5, 9.0 Hz), 3.71 (3H, s), 3.06 (1H, m), 2.93 (1H, m), 2.32
(1H, m), 2.30e1.94 (1H, br), 1.90 (1H, m), 1.70e1.54 (2H, m) ppm.
ꢀ
Hernandez, J. G.; Juaristi, E. Tetrahedron 2011, 67, 6953e6959.
9. See, for example: Huang, X.-Y.; Wang, H.-J.; Shi, J. J. Phys. Chem. A 2010, 114,
1068e1081.
13C NMR (125 MHz, CDCl3)
d 205.8, 170.2, 135.2, 128.6, 128.9,
ꢀ
10. (a) Gryko, D.; Lipinski, R. Adv. Synth. Catal. 2005, 347, 1948e1952; (b) Gryko, D.;
127.3, 68.0, 60.3, 52.7, 47.3, 34.3, 25.9 ppm. HR-ESI-TOF: calcu-
lated for C14H19N2O2S [MþH]þ: 279.1161; found: 279.1166
(1.5 ppm error).
ꢀ
Lipinski, R. Eur. J. Org. Chem. 2006, 3864e3876; (c) Gryko, D.; Zimnicka, M.;
ꢀ
Lipinski, R. J. Org. Chem. 2007, 72, 964e970; (d) Gryko, D.; Saletra, W. J. Org.
ꢀ
ꢀ
Biomol. Chem. 2007, 5, 2148e2153; (e) Gryko, D.; Chrominski, M.; Pielacinska,
D. J. Symmetry 2011, 3, 265e282.
ꢀ
11. (a) Almas¸ i, D.; Alonso, D. A.; Najera, C. Adv. Synth. Catal. 2008, 350, 2467e2472;
4.3.3. (S,S)-Thio-proline-tryptophan methyl ester, 1f. Rf¼0.14 [silica
ꢀ
(b) Almas¸ i, D.; Alonso, D. A.; Balaguer, A. N.; Najera, C. Adv. Synth. Catal. 2009,
gel, DCM/MeOH 30:1], [
a
]
D
22 þ22.4 (c 1.0, CH2Cl2), (FTIR/ATR, cmꢀ1
)
351, 1123e1131.
nmax 3364, 3182, 2947, 2865, 1736, 1509. 1H NMR (500 MHz, CDCl3)
12. (a) Wang, B.; Liu, X. W.; Liu, L. Y.; Chang, W. X.; Li, J. Eur. J. Org. Chem. 2010,
5951e5954; (b) Wang, B.; Chen, G. H.; Liu, L. Y.; Chang, W. X.; Li, J. Adv. Synth.
Catal. 2009, 351, 2441e2448.
13. (a) An, Y.-J.; Zhang, Y.-X.; Wu, Y.; Liu, Z.-M.; Pi, C.; Tao, J.-C. Tetrahedron:
Asymmetry 2010, 21, 688e694; (b) Lei, M.; Xia, S.; Wang, J.; Ge, Z.; Cheng, T.; Li,
R. Chirality 2010, 22, 580e586.
14. See, for example: (a) Li, J.; Yang, G.; Qin, Y.; Yang, X.; Cui, Y. Tetrahedron:
Asymmetry 2011, 22, 613e618; (b) Moorthy, J. N.; Saha, S. Eur. J. Org. Chem. 2009,
739e748; (c) Huang, W.; Tian, H.; Xu, H.; Zheng, L.; Liu, Q.; Zhang, S. Catal. Lett.
2011, 141, 782e876; (d) Yan, J.; Wang, L. Synthesis 2008, 18, 2065e2072.
d
10.27 (1H, br), 8.55 (1H, s), 7.52 (1H, d, J¼7.9 Hz), 7.29 (1H, d,
J¼8.1 Hz), 7.14 (1H, t, J¼7.2 Hz), 7.07 (1H, t, J¼7.6 Hz), 6.91 (1H, d,
J¼2.3 Hz), 5.41 (1H, br), 4.03 (1H, dd, J¼5.5, 9.2 Hz), 3.69 (3H, s),
3.50 (1H, dd, J¼5.5, 14.8 Hz), 3.40 (1H, dd, J¼5.7, 14.8 Hz), 2.77 (1H,
m), 2.44 (1H, m), 2.25 (1H, m), 1.84 (2H, m), 1.48 (1H, m), 1.32 (1H,
m) ppm. 13C NMR (125 MHz, CDCl3)
d 206.0, 171.5, 135.9, 127.4,
122.8, 122.0, 119.4, 118.4, 111.3, 109.4, 67.9, 57.5, 52.5, 47.0, 34.1, 26.5,
25.9 ppm. HR-ESI-TOF: calculated for C17H22N3O2S [MþH]þ:
332.1427; found: 332.1426 (0.4 ppm error).
ꢀ
ꢀ
15. Dziedzic, P.; Zou, W.; Hafren, J.; Cordova, A. Org. Biomol. Chem. 2006, 4, 38e40.
16. Fuentes de Arriba, A. L.; Simon, L.; Raposo, C.; Alcazar, V.; Sanz, F.; Muniz, F. M.;
ꢀ
ꢀ
~
ꢀ
Moran, J. R. Org. Biomol. Chem. 2010, 8, 2979e2985.
17. (a) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Commun. 2006, 2801e2803; (b) Jiang,
Z.; Yang, H.; Han, X.; Luo, J.; Wong, M. W.; Lu, Y. Org. Biomol. Chem. 2010, 8,
1368e1377.
18. (a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2003, 20, 216e242; (b) Zhang, H.-P.;
Shigemori, H.; Ishibashi, M.; Kosaka, T.; Pettit, G. R.; Kamano, Y.; Kobayashi, J.
Tetrahedron 1994, 50, 10201e10206; (c) Kamano, Y.; Zhang, H.-P.; Ichihara, Y.;
Kizu, H.; Komiyama, K.; Pettit, G. R. Tetrahedron Lett. 1995, 36, 2783e2784.
19. Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman, Q. B.; Tomasini, C. J.
Org. Chem. 2005, 70, 7418e7421.
20. The absolute configuration of the products was assigned by comparison with
literature data: (a) Chen, J. R.; Liu, X. P.; Zhu, X. Y.; Li, L.; Qiao, Y. F.; Zhang, J. M.;
Xiao, W. J. Tetrahedron 2007, 63, 10437e10444; (b) Aikawa, K.; Mimura, S.;
Numata, Y.; Mikami, K. Eur. J. Org. Chem. 2011, 62e65.
4.4. Typical procedure for the intermolecular aldol reaction;
ball-mill method
A mixture of catalyst 1d (7 mol %), ketone 2 (0.22 mmol), and
aldehyde 3 (0.2 mmol) was vigorously milled for 6.0e8.0 h at
2760 rpm at ꢀ20 ꢁC in a digital Mixer/Amalgamator fitted with
a reactor made of Nylamid (cylinder, 25 mm long and with a di-
ameter 10 mm) containing one stainless steel ball with a 5 mm
diameter. The crude reaction mixture was purified by flash