L-prolinamides derived from chiral and achiral 1,2-diamines as useful bifunctional organocatalysts for direct diastereo-and enantioselective aldol reaction

Article abstract of DOI:10.1002/ejoc.201000616

Diastereomeric catalysts 5 and epi-5, which differ in the configuration of the stereocenter at the amino component, have been prepared from L-proline and (S)-N²,N²-dibenzyl-3-methylbutane-1,2-diamine or (R)-N¹,N¹

Full text of DOI:10.1002/ejoc.201000616

FULL PAPER
DOI: 10.1002/ejoc.201000616
L
-Prolinamides Derived from Chiral and Achiral 1,2-Diamines as Useful
Bifunctional Organocatalysts for Direct Diastereo- and Enantioselective Aldol
Reaction
Rafael Pedrosa,*[a] José M. Andrés,*[a] Rubén Manzano,[a] and Paula Rodríguez[a]
Dedicated to Professor Josep Font on occasion of his 70th birthday
Keywords: Aldol reactions / Amides / Amines / Asymmetric catalysis / Enantioselectivity / Organocatalysis
Diastereomeric catalysts 5 and epi-5, which differ in the con-
catalyst. A small match/mismatch effect over the stereoselec-
tion was observed, depending on the configuration of the
stereocenters at the proline and diamine components. In ge-
neral, the best results were obtained with catalyst 5, which
has the same configuration at both stereocenters. Under the
same reaction conditions, prolinamide 20, which was synthe-
figuration of the stereocenter at the amino component, have
been prepared from
L
-proline and (S)-N2,N2-dibenzyl-3-
methylbutane-1,2-diamine or (R)-N1,N1-dibenzyl-3-meth-
ylbutane-1,2-diamine, respectively. Diastereomeric prolin-
amides 10 and epi-10, which are regioisomers of 5 and epi-
5, respectively, were obtained from the same starting com-
pounds. All of the catalysts promoted high diastereo- and
enantioselectivity in the cross-aldol reaction between aro-
matic aldehydes and cyclohexanone using acetic acid as co-
sized from
L-proline and ethylene diamine, without
stereocenters at the diamine component, behaved as an ex-
cellent enantioselective organocatalyst, giving the aldol
products in very high diastereo- and enantioselectivity.
di- and tripeptides,[12] have all been successfully used as
organocatalysts in cross-aldol reactions. Very good results
have been also obtained by using prolylsulfonamides, pro-
linethioamides,[13] modified or immobilized prolin-
amides,[14] and prolinamides derived from o-phenylene di-
amines.[15]
In general, the amine component of these prolinamides
is chiral, and it has been observed that stereochemical con-
trol of the aldol reaction is affected by the configuration
of the stereogenic elements in both the amine and proline
components.[4a,5b,6,9a,10] It has also been described that bis-
prolinamides derived from achiral diamines catalyze the al-
dol reaction but with low ee.[5a]
These results led us to consider the preparation of bi-
functional prolinamides derived from chiral diamines with
only one stereocenter and to investigate their use as organo-
catalysts in direct aldol reactions. The idea was to obtain
information on the influence of the stereocenter at the
amine component, and its relative position with respect to
the proline, on the diastereo- and enantioselectivity of the
reaction. To this end, catalysts 5, 10, epi-5, and epi-10 were
prepared starting from diamines 1 and 11, which were de-
rived from - or -valine and -proline. These prolinamides
cover all the possible combinations of stereocenters and re-
gioisomers in the catalysts. For instance, 5 and epi-5, or 10
and epi-10, derived from -proline, differ in the configura-
tion of the stereocenter at the amine component, whereas 5
Introduction
The search for small molecules that are able to act as
catalysts in enantioselective transformations has received
extensive attention during the last ten years,[1] and direct
aldol reactions between two different carbonyl compounds
is probably one of the most studied processes.[2]
Proline was the first organocatalyst used for the aldol
reaction of aldehydes and acetone,[3] but some problems as-
sociated with its solubility in organic solvents, and the pos-
sibility of tuning the reactivity of the catalyst by modifying
the pKa value of the hydrogen-donor unit led to the search
for proline-modified structures acting as organocatalysts.
These compounds are generally prolinamide derivatives
that differ in the nature of the amine component attached
to the carboxylic functionality of proline. In this regard,
prolinamides derived from trans-1,2-diaminocyclohexane,[4]
1,2-diphenylethylenediamines,[5] cinchone derivatives,[6]
1,1Ј-binaphthyl-2,2Ј-diamine,[7] spirodiamines,[8] amino
alcohols,[9] oxazoline derivatives,[10] amino indanes,[11] and
[a] Instituto CINQUIMA (Centro de Innovación en Química y
Materiales Avanzados) and Departamento de Química
Orgánica, Facultad de Ciencias, Universidad de Valladolid,
Dr. Mergelina s/n, 47011 Valladolid, Spain
Fax: +34-983-186324
E-mail: pedrosa@qo.uva.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000616.
View this journal online at
wileyonlinelibrary.com
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Bifunctional Organocatalysts for Selective Aldol Reactions
and 10 or epi-5 and epi-10 are regioisomers that differ in the amides. Epi-5 was obtained by reaction of 11 with p-
the nitrogen atom where the -proline moiety is attached. toluoyl chloride and debenzylation to 13, followed by con-
We have also prepared the enantiomer of epi-10 starting densation with Boc--proline and subsequent deprotection.
from diamine 11 and -proline. For comparative purposes, epi-10 was synthesized from 11 by condensation with Boc-
diamide 20 Ϫ with no stereocenter at the amine chain Ϫ -proline and debenzylation to 17, followed by reaction
was also synthesized from ethylenediamine and -proline.
with p-toluoyl chloride and deprotection.
The catalytic activity of these prolinamides was evaluated
in the direct enantioselective aldol reaction of 4-chlorobenz-
aldehyde and cyclohexanone (Scheme 3); the results are
summarized in Table 1. In general, all the catalysts provided
the anti-aldol product 21a in good to excellent yields (77–
98%) and very good enantio- (91:9 to 98:2) and diastereo-
selectivity (89:11 to 95:5 anti/syn).
Results and Discussion
Diamides 5, 10, and ent-epi-10 were prepared from (S)-
N2,N2-dibenzyl-3-methylbutane-1,2-diamine (1)[16] in four
steps, in moderate to good yields, as summarized in
Scheme 1. The reaction of 1 with Boc--proline led to 2,
which was debenzylated by hydrogenolysis to 3. Condensa-
After preliminary screening to select appropriate experi-
tion of 3 with p-toluoyl chloride yielded 4, which was trans- mental conditions, the reactions were carried out with
formed into 5 by hydrolysis of the Boc group. Reaction of 20 mol-% of catalyst 5 and 20 mol-% of acetic acid as co-
1 with p-toluoyl chloride gave 6, which was transformed catalyst, at –20 °C in 1:1 (v/v) mixtures of cyclohexanone
into 7 by debenzylation and subsequently converted into 10 and the corresponding solvent. The reaction could also be
by sequential condensation with Cbz--proline and depro- performed with only 5 mol-% of catalyst and cocatalyst
tection by hydrogenolysis. Similarly, ent-epi-10 was obtained with only a slight decrease in yield and the diastereo- and
following the same protocol starting from Cbz--proline as enantioselection (entry 4 in Table 1). It was found that
amino acid.
tetrahydrofuran (THF) was a worse solvent than either
The synthesis of epi-5 and epi-10 started from (R)-N1,N1- chloroform or toluene in the reactions using prolinamide 5
dibenzyl-3-methylbutane-1,2-diamine (11)[16] and was also as catalyst; the enantioselection was essentially maintained
carried out in four steps (Scheme 2). The preparation of the in the three solvents, but the diastereoselectivity decreased
two regioisomers only varied in the order of formation of when THF was used (entries 1–3 in Table 1).
Scheme 1. Reagents and conditions: (i) Boc--proline, N,NЈ-dicyclohexylcarbodiimide (DCC), CH2Cl2, 0 °C to room temp. (ii) H2, Pd-
(OH)2/C, MeOH. (iii) p-CH3C6H4COCl, Et3N, CH2Cl2, 0 °C to room temp. (iv) Trifluoroacetic acid (TFA), CH2Cl2, room temp. (v) p-
CH3C6H4COCl, CH2Cl2, 0 °C to room temp. (vi) Cbz--proline, DCC, CH2Cl2, 0 °C to room temp. (vii) Cbz--proline, DCC, CH2Cl2,
0 °C to room temp. (viii) H2, Pd/C (10%), MeOH.
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R. Pedrosa, J. M. Andrés, R. Manzano, P. Rodríguez
FULL PAPER
Scheme 2. Reagents and conditions: (i) p-CH3C6H4COCl, CH2Cl2, 0 °C to room temp. (ii) H2, Pd(OH)2/C, MeOH. (iii) Boc--proline,
DCC, CH2Cl2, 0 °C to room temp. (iv) TFA, CH2Cl2, room temp. (v) p-CH3C6H4COCl, Et3N, CH2Cl2, 0 °C to room temp.
Scheme 3. Direct aldol reaction catalyzed by 5–20.
Small match/mismatch effects were observed by using
epimeric catalysts 10 and epi-10, which differ in the configu-
Table 1. Dependence of er and ee on the catalyst and the solvent.
Entry[a] Catalyst
Solvent
t [h] Yield[b] anti/syn[c] er (anti)[d]
ration at the amine stereocenter. Catalyst 10, which has the
same configuration at the stereocenters of both compo-
nents, gave better yield and diastereoselectivity than epi-10,
although no difference was observed in the enantioselection
when toluene was used as solvent (entries 8 and 10 in
Table 1). In contrast, the yield and both the diastereo- and
enantioselectivity decreased for epi-10 when the reactions
were carried out in chloroform (entries 7 and 9). As ex-
pected, ent-epi-10 (entry 11) behaved in a similar way to
epi-10, but led to the enantiomeric aldol (ent-anti-21a).
These results showed that the stereochemistry of the final
aldol product is determined by the proline component in
the catalyst,[10,11c] and that amines with the same configura-
tion as the proline constitutes a ‘matched’ component that
results in an improved enantioselective organocatalyst.
Interestingly, no noticeable differences were observed in
the reactions with 5 and epi-5 as catalysts (entries 1 and 5
1
2
5
5
5
5
CHCl3
toluene
THF
toluene
CHCl3
toluene
CHCl3
toluene
CHCl3
toluene
48
48
24
48
65
48
46
48
72
48
48
72
48
90
88
98
83
98
96
92
98
72
87
97
77
95
93:7
92:8
90:10
92:8
93:7
94:6
93:7
93:7
91:9
90:10
93:7
89:11
95:5
97:3
98:2
96:4
96:4
97:3
97:3
95:5
95:5
91:9
94:6
92:8
96:4
97:3
3
4[e]
5
epi-5
epi-5
10
10
epi-10
epi-10
ent-epi-10 toluene
20
20
6
7
8
9
10
11
12
13
CHCl3
toluene
[a] Reagents and conditions: organocatalyst (0.1 mmol), AcOH
(0.1 mmol), solvent/cyclohexanone (1:1, 2 mL), 20 min, –20 °C
then aldehyde (0.5 mmol), 24–72 h. [b] Isolated yields. [c] Deter-
mined by H NMR analysis of the crude product. [d] Determined
by chiral HPLC (see conditions in the experimental section). [e]
Reaction performed with 5 mol-% catalyst and 5 mol-% AcOH.
1
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Bifunctional Organocatalysts for Selective Aldol Reactions
versus 2 and 6 in Table 1). These prolinamides, which are 48 h of reaction time to reach the same yields, benzaldehyde
regioisomers of 10 and epi-10, respectively, essentially give required 72 h to give the aldol product 21f in moderate to
the same mixtures of diastereo- and enantiomers, implying good yields (entries 13–15). The less electrophilic p-methyl-
that the match/mismatch effects are not operative in these benzaldehyde is a poor substrate and gave the aldol product
catalysts.
21g in moderate to good yields only after six or seven days
Intrigued by these facts, we prepared 20, which does not of reaction (entries 16 and 17 in Table 2).
contain a stereocenter at the amine component, and tested
it as catalyst in the same reaction. Prolinamide 20 was pre-
pared from ethylene diamine, in three steps, as outlined in
Scheme 4. The diamine was transformed into 18 by treat-
ment with p-toluoyl chloride, followed by condensation
with Boc--proline to 19. Deprotection of 19 with trifluoro-
acetic acid led to 20 in moderate total yield.
Fortunately, compound 20 also works as a catalyst in the
aldol reaction under the same experimental conditions as
described above (entries 12 and 13 in Table 1). In chloro-
form as a solvent, the reaction proceeds in 77% yield, with
moderate diastereoselection (89:11 anti/syn) and excellent
enantioselectivity (96:4). The process leads to the aldol
product anti-21a with excellent yield, diastereo- and
enantioselectivity when toluene was used as solvent.
Table 2. Aldol reaction of cyclohexanone with aldehydes catalyzed
by 5, 10, and 20.
Entry
R
Cat. t [h] Yield[a] Product anti/syn[b,c] ee (anti)[d,e]
1
2
3
4
5
6
7
8
p-Cl
p-Cl
p-Cl
5
10
20
5
20
5
20
5
10
20
5
20
5
10
20
5
48
48
48
24
24
28
22
21
24
21
24
24
72
71
72
144
88
98
95
93
98
95
95
95
96
93
98
98
95
81
63
80
50
21a
21a
21a
21b
21b
21c
21c
21d
21d
21d
21e
21e
21f
21f
21f
21g
21g
92:8
93:7
96
90
95:5 (96:4) 94 (94)
90:10 92
91:9 (99:1) 94 (96)
94:6 92
94:6 (96:4) 92 (94)
o-NO2
o-NO2
m-NO2
m-NO2
p-NO2
p-NO2
p-NO2
p-CN
p-CN
H
91:9
95:5
92
94
9
10
11
12
13
14
15
16
17
93:7 (96:4) 90 (92)
87:13 90
86:14 (95:5) 88 (94)
93:7
94:6
92:8 (83:17) 92 (87)
91:9 92
91:9 (80:20) 92 (77)
92
94
Using the described reaction conditions in toluene, a set
of benzaldehydes with different electronic characteristics
was treated with cyclohexanone by using 5, its regioisomer
10, and 20 as catalysts for comparative purposes, to study
the generality of the cross-aldol reaction (Scheme 5).
The results, summarized in Table 2, show that o-, m-, and
p-nitrobenzaldehydes (entries 4–10 in Table 2) or p-cya-
nobenzaldehyde (entries 11 and 12) are the most reactive,
yielding the aldol products 21b–e in excellent yields after
H
H
p-Me
p-Me
20 168
[a] Isolated yield. [b] Determined by 1H NMR analysis of the crude
product. [c] Numbers in parenthesis correspond to the best dr pre-
viously described for the same reaction with different catalysts in
organic solvents.[4a] [d] Determined by chiral HPLC analysis (see
conditions in the experimental section). [e] Numbers in parenthesis
correspond to the best ee previously described for the same reaction
24 h at –20 °C. Whereas p-chlorobenzaldehyde required with different catalysts in organic solvents.[4a]
Scheme 4. Reagents and conditions: (i) p-CH3C6H4COCl, MeOH, 0 °C, 60 s, 63%. (ii) Boc--proline, DCC, CH2Cl2, 0 °C to room temp.,
87%. (iii) TFA, CH2Cl2, room temp., 80%.
Scheme 5. Direct aldol reaction of aldehydes with cyclohexanone catalyzed by 5, 10, and 20.
Eur. J. Org. Chem. 2010, 5310–5319
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R. Pedrosa, J. M. Andrés, R. Manzano, P. Rodríguez
FULL PAPER
Chiralcel OD Column (250ϫ4.6 mm). UV absorbance was moni-
tored at 220 nm or at 254 nm. Racemic samples were prepared by
using racemic proline as the catalyst in DMF[17] or DMSO.[3c]
The difference in reactivity did not affect the diastereo-
selectivity of the cross-aldol reaction, which was excellent
for all the aldehydes except for p-cyanobenzaldehyde (en-
tries 11 and 12). The enantioselectivity was maintained at
excellent levels for all the studied reactions. Interestingly, no
noticeable changes in either the diastereo- or enantioselec-
tion were observed in the reactions promoted by catalysts 5
and 10, which were derived from a chiral diamine, and cata-
lyst 20, which was derived from achiral ethylene diamine.
Moreover, a comparison between the stereoselection ob-
tained with 20 and the best previously described with a cat-
alyst derived from (R,R)-1,2-cyclohexane diamine[4a] (see
Table 2) showed that the diastereo- and enantioselection
were quite similar for aldehydes with electron-withdrawing
substituents (entries 3, 5, 7, and 9) and better for benzalde-
hyde and 4-methylbenzaldehyde (entries 15 and 17). In con-
trast, the stereodiscrimination was worse for the aldol reac-
tion with 4-cyanobenzaldehyde (entry 11 in Table 2).
Organic compounds were used as received. Solvents were dried and
stored over microwave-activated molecular sieves (4 Å).
(S)-tert-Butyl 2-[(S)-2-(Dibenzylamino)-3-methylbutylcarbamoyl]-
pyrrolidine-1-carboxylate (2): N-Boc--Proline (740 mg, 3.44 mmol,
1.25 equiv.) and DCC (709 mg, 3.44 mmol, 1.5 equiv.) were dis-
solved in dichloromethane (25 mL) and cooled to 0 °C. The solu-
tion was stirred for 30 min, then a solution of 1 (776 mg,
2.75 mmol, 1 equiv.) in dichloromethane (25 mL) was added drop-
wise over 10 min. After the addition was complete, the mixture was
warmed to r.t. and stirred for a further 10 h. After filtration and
removal of solvent under reduced pressure, the residue was purified
by flash column chromatography on silica gel (hexane/EtOAc, 4:1)
to provide prolinamide 2 (1.16 g, 2.42 mmol, 88%) as a colorless
oil; [α]2D3 = –56.4 (c = 1.2, CHCl3). 1H NMR (300 MHz, CDCl3,
330 K): δ = 0.95 (d, J = 6.8 Hz, 3 H), 1.03 (d, J = 6.8 Hz, 3 H),
1.43 (s, 9 H), 1.85 (m, 2 H), 2.03 (m, 2 H), 2.21 (br. s, 1 H), 2.45
(m, 1 H), 3.32 (m, 1 H), 3.42 (m, 2 H), 3.62 (m, 1 H), 3.70 (d, J =
13.6 Hz, 2 H), 3.76 (d, J = 13.6 Hz, 2 H), 4.22 (m, 1 H), 6.58 (br.
s, 1 H), 7.20–7.35 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3,
330 K): δ = 19.8 (CH3), 21.5 (CH3), 24.2 (CH2), 28.0 (CH), 28.3
(CH3), 36.9 (CH2), 47.0 (CH2), 54.4 (CH2), 60.8 (CH), 63.1 (CH),
80.1 (C), 126.7, 128.1, 128.9 (ArCH), 140.0 (ArC), 155.3 (NCO2),
Conclusions
We have prepared six novel prolinamides, derived from
1,2-diamines, which act as organocatalysts in the enantio-
selective direct cross-aldol reaction of aromatic aldehydes
with cyclohexanone. In all cases, the aldol products are ob-
tained with good to excellent yields and stereoselectivities.
Catalyst 10, with the same configuration at the proline and
amine components, led to better diastereo- and enantio-
selectivities than its epimers epi-10 or ent-epi-10. This
match/mismatch effect is less pronounced for catalysts 5
and epi-5. Based on these observations, prolinamide 20 was
prepared from ethylene diamine and tested as an enantiose-
lective catalyst in the same reaction. This compound, which
is cheaper and easier to prepare than the prolinamides de-
rived from chiral diamines, is a good organocatalyst for the
enantioselective aldol reactions, leading to the final adducts
with diastereo- and enantioselectivities as good, or better,
than those previously described.
171.6 (CON) ppm. IR (film): ν = 3336, 2976, 1686, 1397, 1163,
˜
1122, 749, 700 cm–1. HRMS: calcd. for C29H41N3O3Na+ 502.3046;
found 502.3044.
(S)-tert-Butyl 2-[(S)-2-Amino-3-methylbutylcarbamoyl]pyrrolidine-
1-carboxylate (3): To a solution of -prolinamide 2 (1.07 g,
2.23 mmol) in MeOH (22 mL), was added Pd(OH)2-C (320 mg) in
one portion. The mixture was stirred under H2 for 2 h and the
catalyst was removed by filtration and washed with methanol. The
solvent was evaporated under reduced pressure and the residue was
purified by flash column chromatography on silica gel (EtOAc/
methanol, 5:1) to give 3 (548 mg, 1.83 mmol, 82%) as a colorless
oil. [α]2D3 = –28.0 (c = 0.5, CHCl3). 1H NMR (300 MHz, CDCl3,
330 K): δ = 0.95 (d, J = 7.0 Hz, 3 H), 0.97 (d, J = 6.6 Hz, 3 H),
1.46 (s, 9 H), 1.70 (m, 1 H), 1.95 (m, 4 H), 2.74 (br. s, 1 H), 3.05
(m, 1 H), 3.48 (m, 4 H), 3.58 (br. s, 2 H), 4.23 (m, 1 H) ppm. 13C
NMR (75 MHz, CDCl3, 330 K): δ = 17.7 (CH3), 19.1 (CH3), 24.2
(CH2), 28.4 (CH3), 30.0 (CH2), 32.1 (CH), 43.5 (CH2), 47.1 (CH2),
56.6 (CH), 60.8 (CH), 80.2 (C), 155.2 (NCO2), 172.5 (CON) ppm.
IR (film): ν = 3330, 2970, 1688, 1395, 1164, 1124, 772, 734 cm–1.
˜
HRMS: calcd. for C15H29N3O3 + H+ 300.2287; found 300.2281.
Experimental Section
General: 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra
were recorded in CDCl3. Chemical shifts for protons are reported
in ppm from tetramethylsilane, with the residual CHCl3 resonance
as internal reference. Chemical shifts for carbons are reported in
ppm from tetramethylsilane and are referenced to the central car-
bon resonance of the solvent. Data are reported as follows: chemi-
cal shift, multiplicity (s for singlet, d for doublet, t for triplet, q for
quartet, m for multiplet; br. broad), coupling constants in Hertz,
and integration. Specific rotations were measured using a 5-mL cell
with a 1-dm path length, and a sodium lamp, and concentration is
given in g per 100 mL. Melting points were obtained with open
capillary tubes. Flash chromatography was carried out using silica
gel (230–240 mesh). Chemical yields refer to pure isolated sub-
stances. TLC analysis was performed with glass-backed plates
coated with silica gel 60 containing an F254 indicator, and visual-
ized by either UV irradiation or by staining with phosphomolybdic
acid solution. Chiral HPLC analysis was performed with a Daicel
(S)-tert-Butyl
amoyl]pyrrolidine-1-carboxylate (4):
2-[(S)-3-Methyl-2-(4-methylbenzamido)butylcarb-
mixture of (497 mg,
A
3
1.66 mmol) and triethylamine (0.28 mL, 2 mmol, 1.2 equiv.) in
dichloromethane (8 mL) was cooled to 0 °C and p-toluoyl chloride
(0.27 mL, 2 mmol, 1.2 equiv.) was added dropwise. After the ad-
dition was complete, the mixture was warmed to r.t. and stirred
overnight. The resulting solution was quenched with aq. sat. am-
monium chloride (8 mL) and the aqueous phase was extracted with
dichloromethane (3ϫ10 mL). The combined organic layers were
dried with anhydrous MgSO4 and the solvents were removed under
vacuum. The residue was purified by flash column chromatography
on silica gel (hexane/EtOAc, 1:1) to give 4 (555 mg, 1.33 mmol,
80%) as a colorless solid; m.p. 120–121 °C (hexane/EtOAc); [α]2D3
=
1
–74.3 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3, 330 K): δ =
0.99 (d, J = 6.6 Hz, 3 H), 1.00 (d, J = 7.0 Hz, 3 H), 1.38 (s, 9 H),
1.89 (m, 5 H), 2.36 (s, 3 H), 3.45 (m, 4 H), 4.03 (m, 1 H), 4.15 (m,
1 H), 6.54 (br. s, 1 H), 6.87 (br. s, 1 H), 7.19 (d, J = 7.9 Hz, 2 H),
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Bifunctional Organocatalysts for Selective Aldol Reactions
7.67 (d, J = 7.9 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 300 K): (R)-Benzyl 2-[(S)-3-Methyl-1-(4-methylbenzamido)butan-2-ylcarb-
δ = 18.6 (CH3), 19.1 (CH3), 21.2 (CH3), 24.1 (CH2), 28.4 (CH3),
30.7 (CH), 41.7 (CH2), 47.0 (CH2), 56.1 (CHN), 60.6 (CHCO), 80.2 (288 mg, 1.31 mmol) with Cbz--proline in the presence of DCC
(C), 127.1, 129.1 (ArCH), 132.0, 141.6 (ArC), 155.1 (NCO2), 167.7 by the procedure described for the preparation of 2 and purified
amoyl]pyrrolidine-1-carboxylate (8): Obtained by reaction of 7
(CON), 173.7 (CON) ppm. IR (KBr): ν = 3314, 2972, 1662, 1542, by flash column chromatography on silica gel (EtOAc/hexane, 1:1);
˜
1404, 1165, 752 cm–1. HRMS: calcd. for C23H35N3O4Na 440.2525;
found 440.2522.
yield 527 mg (1.17 mmol, 89%); colorless solid; m.p. 147–148 °C
(hexane/EtOAc); [α]2D3 = +44.0 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3, 330 K): δ = 0.92 (d, J = 6.6 Hz, 3 H), 0.96 (d,
J = 7.0 Hz, 3 H), 1.80 (m, 5 H), 2.34 (s, 3 H), 3.54 (m, 4 H), 3.91
(m, 1 H), 4.28 (dd, J = 8.3, 3.5 Hz, 1 H), 5.06 (m, 2 H), 6.60 (br.
s, 1 H), 6.94 (br. s, 1 H), 7.16 (d, J = 8.0 Hz, 2 H), 7.30 (m, 5 H),
7.68 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3, 330 K):
δ = 18.5 (CH3), 19.5 (CH3), 21.4 (CH3), 24.4 (CH2), 29.8 (CH2),
30.7 (CH), 43.3 (CH2), 47.4 (CH2), 55.4 (CH), 61.3 (CH), 67.6
(CH2), 127.3, 128.0, 128.3, 128.7, 129.2 (ArCH), 131.9, 136.7, 141.7
(ArC), 156.0 (NCO2), 167.9 (CON), 173.4 (CON) ppm. IR (KBr):
(S)-N-[(S)-3-Methyl-2-(4-methylbenzamido)butyl]pyrrolidine-2-carb-
oxamide (5): Compound 4 (501 mg, 1.2 mmol) was dissolved in a
mixture of TFA/CH2Cl2 (1:4, 3 mL), and stirred at r.t. for 2 h. The
mixture was basified with concentrated ammonia solution and ex-
tracted with dichloromethane (3ϫ10 mL). After removal of the
solvent under reduced pressure, the residue was purified by flash
column chromatography on silica gel (EtOAc/MeOH, 5:1) to yield
5 (293 mg, 0.92 mmol, 77%) as a colorless solid; m.p. 161–162 °C
(hexane/EtOAc); [α]2D3 = –52.1 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 0.97 (d, J = 6.9 Hz, 6 H), 1.62 (m, 2 H),
1.82 (m, 1 H), 1.89 (m, 1 H), 2.04 (m 1 H), 2.22 (br. s, 1 H), 2.34
(s, 3 H), 2.86 (m, 2 H), 3.22 (m, 1 H), 3.57 (m, 2 H), 4.04 (m, 1
ν = 3282, 3133, 2962, 1702, 1648, 1549, 1419, 1360, 1126, 750,
˜
740, 698 cm–1. HRMS: calcd. for C26H33N3O4Na+ 474.2369; found
474.2360.
H), 6.91 (d, J = 8.6 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 2 H), 7.67 (d, J (S)-Benzyl 2-[(S)-3-Methyl-1-(4-methylbenzamido)butan-2-ylcarb-
= 8.0 Hz, 2 H), 7.97 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): amoyl]pyrrolidine-1-carboxylate (9): Obtained by reaction of 7
δ = 18.6 (CH3), 18.8 (CH3), 21.3 (CH3), 25.9 (CH2), 30.5 (CH2),
30.7 (CH), 40.5 (CH2), 47.0 (CH2), 56.0 (CHN), 60.2 (CHCO),
(465 mg, 2.11 mmol) with Cbz--proline in the presence of DCC
by the procedure described for the preparation of 2 and purified
126.9, 129.0 (ArCH), 131.6, 141.4 (ArC), 167.6 (CON), 176.7 by flash column chromatography on silica gel (EtOAc/hexane, 2:1);
(CON) ppm. IR (KBr): ν = 3305, 2964, 2869, 1658, 1630, 1548,
yield 890 mg (1.97 mmol, 93%); colorless solid; m.p. 151–152 °C
(hexane/EtOAc). [α]2D3 = –51.5 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3, 330 K): δ = 0.92 (d, J = 6.8 Hz, 3 H), 0.96 (d,
J = 6.6 Hz, 3 H), 1.93 (m, 4 H), 2.20 (m, 1 H), 2.38 (s, 3 H), 3.35
(m, 1 H), 3.52 (m, 2 H), 3.64 (m, 1 H), 3.87 (m, 1 H), 4.32 (dd, J
= 7.8, 3.2 Hz, 1 H), 5.06 (d, J = 12.3 Hz, 1 H), 5.15 (d, J = 12.3 Hz,
1 H), 6.50 (br. s, 1 H), 6.93 (br. s, 1 H), 7.20 (d, J = 8.1 Hz, 2 H),
7.30 (s, 5 H), 7.71 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 18.2 (CH3), 19.3 (CH3), 21.3 (CH3), 28.6 (CH2), 30.2
(CH), 33.9 (CH2), 43.2 (CH2), 47.0 (CH2), 55.0 (CH), 60.8 (CH),
67.3 (CH2), 127.1, 127.8, 128.1, 128.4, 129.0 (ArCH), 131.3, 136.2,
141.5 (ArC), 156.0 (NCO2), 167.6 (CON), 172.8 (CON) ppm. IR
˜
1434, 841, 679 cm–1. HRMS: calcd. for C18H27N3O2 + H+
318.2182; found 318.2181.
(S)-N-[2-(Dibenzylamino)-3-methylbutyl]-4-methylbenzamide (6): To
a cooled (0 °C) solution of 1 (847 mg, 3 mmol) in dichloromethane
(12 mL) was slowly added p-toluoyl chloride (0.48 mL, 3.6 mmol,
1.2 equiv.). After the addition was complete, the mixture was
warmed to r.t. and stirred overnight. The resulting solution was
basified with 2  ammonia (10 mL) and the aqueous phase was
extracted with dichloromethane (3ϫ10 mL). The combined or-
ganic layers were washed with water, dried with anhydrous MgSO4
and the solvents were removed under vacuum. The residue was
purified by flash column chromatography on silica gel (hexane/
EtOAc, 8:1) to give 6 (981 mg, 2.45 mmol, 82%) as a colorless oil;
(KBr): ν = 3299, 1715, 1662, 1636, 1543, 1423, 1355, 1120 cm–1.
˜
HRMS: calcd. for C26H33N3O4Na+ 474.2369; found 474.2354.
1
[α]2D3 = –64.6 (c = 1.6, CHCl3). H NMR (300 MHz, CDCl3): δ =
(S)-N-[(S)-3-Methyl-1-(4-methylbenzamido)butan-2-yl]pyrrolidine-
2-carboxamide (10): Compound 9 (841 mg, 1.86 mmol) was deben-
zylated by hydrogenation with Pd/C (10%) in MeOH and purified
by flash column chromatography on silica gel (EtOAc/methanol,
5:1); yield 529 mg (1.67 mmol, 89 %); colorless solid; m.p. 115–
1.05 (d, J = 6.7 Hz, 3 H), 1.14 (d, J = 6.8 Hz, 3 H), 2.22 (m, 1 H),
2.44 (s, 3 H), 2.62 (m, 1 H), 3.27 (m, 1 H), 3.65 (d, J = 13.2 Hz, 2
H), 3.66 (m, 1 H), 3.89 (d, J = 13.2 Hz, 2 H), 6.52 (br. s, 1 H),
7.15–7.30 (m, 12 H), 7.49 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 20.0 (CH3), 21.3 (CH3), 22.7 (CH3), 27.6 116 °C (hexane/EtOAc); [α]2D3 = –28.0 (c 1.0, CHCl3). 1H NMR
(CH), 37.9 (CH2), 53.9 (CH2), 62.3 (CH), 126.8, 127.0, 128.4, (300 MHz, CDCl3): δ = 0.97 (d, J = 6.8 Hz, 3 H), 0.98 (d, J =
128.9, 129.1 (ArCH), 131.8, 139.9, 141.3 (ArC), 167.0 (CON) ppm.
6.8 Hz, 3 H), 1.68 (m, 2 H), 1.88 (m, 2 H), 2.12 (m, 1 H), 2.35 (s,
3 H), 2.65 (br. s, 1 H), 2.90 (dt, J = 10.2, 6.2 Hz, 1 H), 3.00 (dd, J
= 10.2, 6.9 Hz, 1 H), 3.50 (m, 2 H), 3.70 (dd, J = 9.2, 5.1 Hz, 1 H),
3.88 (m, 1 H), 7.18 (d, J = 8.1 Hz, 2 H), 7.53 (br. s, 1 H), 7.69 (d,
J = 8.1 Hz, 2 H), 8.00 (d, J = 8.8 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 18.0 (CH3), 19.5 (CH3), 21.3 (CH3), 25.9
(CH2), 30.2 (CH), 30.7 (CH2), 44.4 (CH2), 47.1 (CH2), 54.0 (CH),
60.2 (CH), 126.9, 129.0 (ArCH), 131.2, 141.4 (ArC), 167.5 (CON),
IR (film): ν = 3343, 2957, 1644, 1494, 1454, 1286, 749, 700 cm–1.
˜
HRMS: calcd. for C27H32N2ONa+ 423.2412; found 423.2407.
(S)-N-(2-Amino-3-methylbutyl)-4-methylbenzamide (7): Obtained
by hydrogenation of 6 (933 mg, 2.33 mmol) with Pd(OH)2-C in
MeOH by using the procedure described for the preparation of 3,
and purified by flash column chromatography on silica gel (EtOAc/
methanol, 5:1); yield 489 mg (2.22 mmol, 95%); colorless oil; [α]2D3
176.7 (CON) ppm. IR (KBr): ν = 3291, 2957, 1636, 1551, 834,
˜
1
= +34.0 (c = 1.2, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.94
670 cm–1. HRMS: calcd. for C18H27N3O2 + H+ 318.2182; found
318.2176.
(d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H), 1.65 (m, 1 H), 1.85
(br. s, 2 H), 2.37 (s, 3 H), 2.67 (m, 1 H), 3.06 (m, 1 H), 3.70 (ddd,
J = 13.4, 6.6, 3.7 Hz, 1 H), 7.05 (br. s, 1 H), 7.20 (d, J = 8.1 Hz, 2
(R)-N-[(S)-3-Methyl-1-(4-methylbenzamido)butan-2-ylcarbamoyl]-
H), 7.70 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ pyrrolidine-1-carboxylate (ent-epi-10): Compound 8 (497 mg,
= 18.5 (CH3), 21.3 (CH3), 29.8 (CH), 40.8 (CH2), 57.9 (CH), 127.4, 1.1 mmol) was deprotected by hydrogenation with Pd/C (10%) in
128.9 (ArCH), 130.7, 141.9 (ArC), 168.2 (CON) ppm. IR (film): ν MeOH and purified by flash column chromatography on silica gel
˜
= 3311, 2959, 2873, 1636, 1545, 1306, 838, 752 cm–1. HRMS: calcd.
for C13H20N2O + H+ 221.1654; found 221.1643.
(EtOAc/methanol, 5:1); yield 210 mg (0.66 mmol, 60%); colorless
solid; m.p. 140–141 °C (hexane/EtOAc); [α]2D3 = +75.6 (c = 1.0,
Eur. J. Org. Chem. 2010, 5310–5319
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5315

R. Pedrosa, J. M. Andrés, R. Manzano, P. Rodríguez
FULL PAPER
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 0.99 (d, J = 6.8 Hz, 3 (300 MHz, CDCl3): δ = 1.00 (d, J = 7.0 Hz, 6 H), 1.46 (m, 2 H),
H), 1.00 (d, J = 6.8 Hz, 3 H), 1.59 (m, 2 H), 1.71 (m, 1 H), 1.91
1.55 (m, 2 H), 1.90 (m, 2 H), 2.39 (s, 3 H), 2.78 (m, 1 H), 2.91 (m,
(m, 1 H), 2.07 (m, 1 H), 2.36 (s, 3 H), 2.89 (m, 1 H), 2.98 (m, 1
1 H), 3.17 (m, 1 H), 3.68 (m, 2 H), 4.09 (m, 1 H), 6.73 (d, J =
H), 3.10 (br. s, 1 H), 3.53 (m, 2 H), 3.83 (dd, J = 9.1, 5.5 Hz, 1 H), 9.2 Hz, 1 H), 7.22 (d, J = 7.9 Hz, 2 H), 7.71 (d, J = 8.3 Hz, 2 H),
3.91 (m, 1 H), 7.20 (d, J = 8.0 Hz, 2 H), 7.47 (br. s, 1 H), 7.71 (d,
J = 8.2 Hz, 2 H), 8.00 (d, J = 8.7 Hz, 1 H) ppm. HRMS: calcd.
for C18H27N3O2+ H+ 318.2182; found 318.2175.
8.02 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.7 (CH3),
19.1 (CH3), 21.4 (CH3), 25.9 (CH2), 30.7 (CH2), 31.1 (CH), 40.4
(CH2), 47.1 (CH2), 56.1 (CH), 60.4 (CH), 127.1, 129.1 (ArCH),
131.5, 141.6 (ArC), 167.6 (CON), 176.9 (CON) ppm. HRMS:
calcd. for C18H27N3O2 + H+ 318.2182; found 318.2157.
(R)-N-(1-Dibenzylamino)-3-(methylbutan-2-yl)-4-methylbenzamide
(12): Prepared by reaction of diamine 11 (565 mg, 2.0 mmol) with
p-toluoyl chloride by the procedure described for the preparation
of 6 and purified by flash column chromatography on silica gel
(S)-tert-Butyl 2-[(R)-1-(Dibenzylamino)-3-methylbutan-2-ylcarb-
amoyl]pyrrolidine-1-carboxylate (15): Obtained by reaction of 11
(EtOAc/hexane, 8:1); yield 697 mg (1.74 mmol, 87%); colorless so- (904 mg, 3.2 mmol) with Boc--proline in the presence of DCC by
lid; m.p. 154–156 °C (hexane/EtOAc); [α]2D3 = +5.3 (c = 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.79 (d, J = 6.9 Hz, 3 H), 0.87
(d, J = 6.9 Hz, 3 H), 2.05 (m, 1 H), 2.45 (s, 3 H), 2.46 (m, 1 H),
2.54 (dd, J = 13.1, 5.7 Hz, 1 H), 3.43 (d, J = 13.3 Hz, 2 H), 3.75
(d, J = 13.3 Hz, 2 H), 4.28 (m, 1 H), 5.80 (d, J = 8.2 Hz, 1 H),
7.20–7.40 (m, 12 H), 7.63 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR
the procedure described for the preparation of 2 and purified by
flash column chromatography on silica gel (EtOAc/hexane, 4:1);
yield 1.51 g (3.15 mmol, 98%); colorless oil; [α]2D3 = –35.8 (c = 1.3,
CHCl3). 1H NMR (300 MHz, CDCl3, 330 K): δ = 0.69 (d, J =
7.0 Hz, 3 H), 0.86 (d, J = 7.0 Hz, 3 H), 1.46 (s, 9 H), 1.94 (m, 4
H), 2.30 (m, 1 H), 2.40 (dd, J = 13.2, 7.9 Hz, 1 H), 2.51 (dd, J =
(75 MHz, CDCl3): δ = 17.4 (CH3), 18.9 (CH3), 21.4 (CH3), 29.9 13.2, 6.1 Hz, 1 H), 3.40 (m, 2 H), 3.61 (m, 4 H), 4.14 (m, 1 H),
(CH), 51.7 (CH), 54.0 (CH2), 58.5 (CH2), 126.8, 126.9, 128.2, 129.0
4.30 (dd, J = 8.3, 2.8 Hz, 1 H), 6.22 (br. s, 1 H), 7.20–7.35 (m, 10
(ArCH), 132.2, 139.3, 141.5 (ArC), 167.3 (CON) ppm. IR (KBr): H) ppm. 13C NMR (75 MHz, CDCl3, 330 K): δ = 16.8 (CH3), 19.6
ν = 3343, 3164, 1670, 1617, 1570, 1413, 1397, 840 cm–1. HRMS: (CH3), 24.5 (CH2), 28.7 (CH3), 30.0 (CH), 47.5 (CH2), 52.1 (CH),
˜
calcd. for C27H32N2O + H+ 401.2593; found 401.2595.
55.5 (CH2), 59.0 (CH2), 61.3 (CH), 80.6 (C), 127.1, 128.4, 129.3
(ArCH), 139.6 (ArC), 155.7 (CO2tBu), 172.1 (CON) ppm. IR
(R)-N-(1-Amino-3-methylbutan-2-yl)-4-methylbenzamide (13): Com-
pound 12 (561 mg, 1.4 mmol) was debenzylated by hydrogenation
with Pd(OH)2-C (10%) in MeOH by the procedure described for
the preparation of 3 and purified by flash column chromatography
on silica gel (EtOAc/methanol, 5:1); yield 293 mg (1.33 mmol,
(film): ν = 3327, 2961, 1698, 1393, 1164, 748, 700 cm–1. HRMS:
˜
calcd. for C29H41N3O3 + H+ 480.3226; found 480.3213.
(S)-tert-Butyl 2-[(R)-1-Amino-3-methylbutan-2-ylcarbamoyl]pyrrol-
idine-1-carboxylate (16): Obtained by hydrogenation of 15 (1.48 g,
3.04 mmol) with Pd(OH)2-C in MeOH by the procedure described
95%); colorless solid; m.p. 173–174 °C (hexane/EtOAc); [α]2D3
=
+13.1 (c = 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.94 (d, for the preparation of 3 and purified by flash column chromatog-
J = 6.8 Hz, 3 H), 0.95 (d, J = 6.7 Hz, 3 H), 1.88 (m, 1 H), 2.37 (s, raphy on silica gel (EtOAc/methanol, 5:1); yield 820 mg
3 H), 2.90 (d, J = 5.7 Hz, 2 H), 3.19 (br. s, 2 H), 3.98 (m, 1 H),
(2.74 mmol, 90%); colorless solid; m.p. 103–104 °C; [α]2D3 = –35.3
1
6.78 (d, J = 9.0 Hz, 1 H), 7.19 (d, J = 8.1 Hz, 2 H), 7.72 (d, J = (c = 1.0, CHCl3). H NMR (300 MHz, CD3OD, 330 K): δ = 0.97
8.1 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.6 (CH3), (d, J = 6.6 Hz, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.46 (s, 9 H), 1.92
19.3 (CH3), 21.2 (CH3), 30.2 (CH), 42.3 (CH2), 56.0 (CH), 127.1,
(m, 4 H), 2.24 (m, 1 H), 2.96 (dd, J = 13.2, 11.0 Hz, 1 H), 3.24
(dd, J = 13.2, 3.1 Hz, 1 H), 3.48 (m, 2 H), 3.94 (m, 1 H), 4.20 (dd,
J = 7.9, 5.3 Hz, 1 H), 4.30 (br. s, 1 H) ppm. 13C NMR (75 MHz,
CD3OD, 330 K): δ = 18.8 (CH3), 19.7 (CH3), 25.5 (CH2), 29.0
(CH3), 31.6 (CH2), 31.7 (CH), 43.9 (CH2), 48.6 (CH2), 54.6 (CH),
61.9 (CH), 82.0 (C), 156.9 (CO2tBu), 176.5 (CON) ppm. IR (KBr):
128.9 (ArCH), 131.4, 141.6 (ArC), 168.0 (CON) ppm. IR (KBr): ν
˜
= 3340, 2873, 1635, 1527, 1503, 834, 755 cm–1. HRMS: calcd. for
C13H20N2O + H+ 221.1654; found 221.1648.
(S)-tert-Butyl 2-[(R)-3-Methyl-2-(4-methylbenzamido)butylcarb-
amoyl]pyrrolidine-1-carboxylate (14): Obtained by reaction of 13
(295 mg, 1.34 mmol) with Boc--proline in the presence of DCC
by the procedure described for the preparation of 2 and purified
by flash column chromatography on silica gel (EtOAc/hexane, 1:1);
yield 459 mg (1.1 mmol, 82%); colorless oil; [α]2D3 = –39.3 (c = 1.0,
CHCl3). 1H NMR (300 MHz, CDCl3, 330 K): δ = 1.02 (d, J =
6.6 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 1.45 (s, 9 H), 1.69 (m, 2
H), 1.91 (m, 2 H), 2.07 (m, 1 H), 2.39 (s, 3 H), 3.30 (m, 3 H), 3.67
(m, 1 H), 4.07 (m, 1 H), 4.22 (dd, J = 8.8, 3.3 Hz, 1 H), 6.49 (br.
s, 1 H), 6.83 (br. s, 1 H), 7.21 (d, J = 7.9 Hz, 2 H), 7.72 (d, J =
ν = 3448, 3220, 2975, 1670, 1420, 1394, 1164, 924, 733 cm–1
.
˜
HRMS: calcd. for C15H29N3O3 + H+ 300.2287; found 300.2284.
(S)-tert-Butyl 2-[(R)-3-Methyl-1-(4-methylbenzamido)butan-2-yl-
carbamoyl]pyrrolidine-1-carboxylate (17): Prepared by reaction of
compound 16 (748 mg, 2.5 mmol) with p-toluoyl chloride in the
presence of Et3N by the procedure described for the preparation of
4 and purified by flash column chromatography on silica gel
(EtOAc/hexane, 3:2); yield 741 mg (1.78 mmol, 71%); colorless so-
lid; m.p. 96–97 °C (from hexane/EtOAc); [α]2D3 = –72.4 (c = 1.4,
7.9 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.8 (CH3), CHCl3). H NMR (300 MHz, CDCl3): δ = 0.98 (d, J = 6.6 Hz, 3
1
19.4 (CH3), 21.4 (CH3), 24.2 (CH2), 28.6 (CH3), 29.8 (CH2), 31.0
(CH), 41.5 (CH2), 47.2 (CH2), 56.2 (CH), 61.0 (CH), 80.6 (C),
127.3, 129.2 (ArCH), 132.1, 141.8 (ArC), 155.5 (CO2tBu), 167.7
H), 1.01 (d, J = 6.6 Hz, 3 H), 1.42 (s, 9 H), 1.72 (m, 2 H), 1.90 (m,
2 H), 2.11 (m, 1 H), 2.35 (s, 3 H), 3.33 (m, 2 H), 3.54 (m, 2 H),
3.91 (m, 1 H), 4.24 (dd, J = 8.3, 3.1 Hz, 1 H), 6.69 (br. s, 1 H),
6.98 (br. s, 1 H), 7.16 (d, J = 7.9 Hz, 2 H), 7.68 (d, J = 7.9 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.1 (CH3), 19.3 (CH3),
21.1 (CH3), 24.1 (CH2), 28.3 (CH3), 29.2 (CH2), 30.4 (CH), 43.3
(CH2), 47.1 (CH2), 55.0 (CH), 60.8 (CH), 80.4 (C), 127.1, 129.0
(ArCH), 131.8, 141.4 (ArC), 155.4 (CO2tBu), 167.5 (CON), 173.6
(CON), 173.8 (CON) ppm. IR (film): ν = 3318, 2972, 1661, 1538,
˜
1505, 1392, 1364, 1164, 752, 733 cm–1. HRMS: calcd. for
C23H36N3O4Na+ 440.2525; found 440.2518.
(S)-N-[(R)-3-Methyl-2-(4-methylbenzamido)butyl]pyrrolidine-2-
carboxamide (epi-5): Prepared by reaction of 14 (434 mg,
1.04 mmol) with TFA in CH2Cl2 by the procedure described for
the preparation of 5 and purified by flash column chromatography
on silica gel (EtOAc/methanol, 5:1); yield 248 mg (0.78 mmol,
75%); colorless oil; [α]2D3 = –33.4 (c = 1.0, CHCl3). 1H NMR
(CON) ppm. IR (KBr): ν = 3311, 2960, 1699, 1651, 1543, 1393,
˜
1162, 756 cm–1.
(S)-N-[(R)-3-Methyl-1-(4-methylbenzamido)butan-2-yl]pyrrolidine-
2-carboxamide (epi-10): Prepared by reaction of 17 (710 mg,
5316
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5310–5319

Bifunctional Organocatalysts for Selective Aldol Reactions
1.7 mmol) with TFA in CH2Cl2 by the procedure described for the
60.4 (CH), 127.1, 129.1 (ArCH), 131.3, 141.6 (ArC), 167.7 (CON),
177.5 (CON) ppm. IR (KBr): ν = 3328, 3290, 2939, 1637, 1540,
preparation of 5 and purified by recrystallization from hexane/
˜
EtOAc; yield 410 mg (1.29 mmol, 76%); colorless solid; m.p. 141– 1216, 835 cm–1. HRMS: calcd. for C15H21N3O2 + H+ 276.1712;
142 °C; [α]2D3 = –78.3 (c = 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 1.00 (d, J = 6.6 Hz, 3 H), 1.02 (d, J = 6.6 Hz, 3 H),
1.56 (m, 2 H), 1.71 (m, 1 H), 1.93 (m, 1 H), 2.05 (m, 1 H), 2.38 (s,
3 H), 2.85 (m, 1 H), 2.96 (m, 1 H), 3.53 (m, 2 H), 3.76 (dd, J =
9.2, 5.3 Hz, 1 H), 3.91 (m, 1 H), 7.21 (d, J = 7.9 Hz, 2 H), 7.43 (br.
s, 1 H), 7.74 (d, J = 7.9 Hz, 2 H), 7.97 (d, J = 8.8 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 18.5 (CH3), 19.6 (CH3), 21.5
(CH3), 26.1 (CH2), 30.4 (CH), 31.0 (CH2), 44.6 (CH2), 47.2 (CH2),
54.0 (CH), 60.6 (CH), 127.1, 129.2 (ArCH), 131.3, 141.6 (ArC),
found 276.1702.
General Procedure for Enantioselective Aldol Reaction: The catalyst
(0.1 mmol) and AcOH (0.1 mmol) were stirred in solvent/cyclo-
hexanone (1:1, 2 mL) for 20 min at –20 °C. The corresponding al-
dehyde (0.5 mmol) was added and the mixture was stirred for 24–
72 h. The reaction mixture give pure aldol adduct after flash col-
umn chromatography on silica gel.
The diastereoselectivity was determined by 1H NMR analysis of
the crude aldol product after short column chromatography purifi-
cation to remove the cyclohexanone and the catalyst. The enantio-
meric excess was determined by chiral HPLC analysis using a
Daicel Chiralpak OD column with a mixture of hexane/2-propanol
as eluting solvents. The absolute stereochemistry was determined
by comparison with the literature data.
167.5 (CON), 177.3 (CON) ppm. IR (KBr): ν = 3361, 3275, 2959,
˜
1647, 1559, 1526, 1140, 1102, 717, 670 cm–1. HRMS: calcd. for
C18H27N3O2 + H+ 318.2182; found 318.2176.
N-(2-Aminoethyl)-4-methylbenzamide
(18):
Ethylenediamine
(1.6 mL, 24 mmol, 1.2 equiv.) was added in one portion to a vigor-
ously stirred solution of the p-toluoyl chloride (2.6 mL, 20 mmol)
in methanol (100 mL) in an ice-water bath. Stirring was continued
for 60 s, then the reaction was quenched with 10% NaOH (10 mL).
The heterogeneous mixture was stirred at r.t. for 5 min and the
methanol was removed under vacuum. The resulting aqueous
phase was diluted with water and extracted with chloroform
(3ϫ25 mL). The combined organic layers were washed with water,
dried with anhydrous MgSO4 and the solvents were removed under
vacuum. The residue was purified by flash column chromatography
on silica gel (CH2Cl2/methanol, 3:2). to give 18 (2.24 g, 12.6 mmol,
2-[(4-Chlorophenyl)hydroxymethyl]cyclohexanone
(21a):[10,18,19]
Yield 88%; ratio anti/syn = 92:8. anti-Diastereomer (2S,1ЈR). 1H
NMR (300 MHz, CDCl3): δ = 1.26–2.11 (m, 6 H), 2.31–2.49 (m, 2
H), 2.52–2.59 (m, 1 H), 3.61 (s, 1 H), 4.76 (d, J = 8.4 Hz, 1 H),
7.25 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 8.8 Hz, 2 H) ppm. HPLC
analysis Chiracel OD (hexane/iPrOH = 95:5; 1.0 mL/min; 220 nm;
20 °C) tR = 14.3 min (major) and tR = 21.6 min (minor); er = 98:2;
[α]D = +23.7 (c = 1.1, CHCl3). syn-Diastereomer: 1H NMR
(300 MHz, CDCl3): δ = 1.49–2.09 (m, 6 H), 2.32–2.46 (m, 2 H),
2.53–2.57 (m, 1 H), 2.92 (br. s, 1 H), 5.34 (d, J = 2.0 Hz, 1 H), 7.23
(d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.4 Hz, 2 H) ppm.
1
63%) as a colorless oil. H NMR (300 MHz, CDCl3): δ = 2.33 (s,
5 H), 2.87 (m, 2 H), 3.45 (m, 2 H), 7.15 (d, J = 8.3 Hz, 2 H), 7.25
(br. s, 1 H), 7.68 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.5 (CH3), 41.3 (CH2), 42.2 (CH2), 127.1, 129.2
2-[Hydroxy(2-nitrophenyl)methyl]cyclohexanone
(21b):[12b,19,20]
Yield 98%; ratio anti/syn = 91:9. anti-Diastereomer (2S,1ЈR): 1H
NMR (300 MHz, CDCl3): δ = 1.57–1.88 (m, 6 H), 2.07–2.13 (m, 1
H), 2.33–2.49 (m, 2 H), 2.74–2.78 (m, 1 H), 5.45 (d, J = 7.0 Hz, 1
H), 7.44 (t, J = 7.5 Hz, 1 H), 7.76 (t, J = 7.5 Hz, 1 H), 7.77 (d, J
= 8.1 Hz, 1 H), 7.85 (d, J = 8.1 Hz, 1 H) ppm. HPLC analysis
Chiracel OD (hexane/iPrOH = 95:5; 1.0 mL/min; 220 nm; 20 °C)
(ArCH), 131.7, 141.9 (ArC), 168.0 (CON) ppm. IR (KBr): ν =
˜
3293, 2924, 1636, 1544, 1505, 1305, 838, 752 cm–1. HRMS: calcd.
for C10H14N2ONa+ 201.1004; found 201.0996.
(S)-tert-Butyl 2-[2-(4-Methylbenzamido)ethylcarbamoyl]pyrrolidine-
1-carboxylate (19): Obtained by reaction of 18 (1.03 g, 5.8 mmol)
with Boc--proline (1.50 g, 6.96 mmol, 1.25 equiv.) in the presence
of DCC (1.43 g, 6.96 mmol, 1.25 equiv.) by the procedure described
for the preparation of 2 and purified by flash column chromatog-
raphy on silica gel (EtOAc); yield 1.89 g (5.05 mmol, 87%); color-
less oil; [α]2D3 = –21.9 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3,
330 K): δ = 1.39 (s, 9 H), 1.83 (m, 2 H), 2.00 (m, 2 H), 2.34 (s, 3
H), 3.50 (m, 6 H), 4.17 (m, 1 H), 6.97 (br. s, 1 H), 7.16 (d, J =
7.9 Hz, 2 H), 7.23 (br. s, 1 H), 7.70 (d, J = 7.9 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3, 300 K): δ = 21.4 (CH3), 24.4 (CH2), 28.5
(CH3), 29.9 (CH2), 39.9 (CH2), 41.0 (CH2), 47.3 (CH2), 61.0 (CH),
127.3, 129.2 (ArCH), 131.8, 141.7 (ArC), 155.3 (NCO2), 168.0
tR = 17.8 min (major) and tR = 21.8 min (minor); er = 97:3; [α]D
=
+36.7 (c = 1.3, CHCl3). syn-Diastereomer: 1H NMR (300 MHz,
CDCl3): δ = 1.50–1.89 (m, 6 H), 2.08–2.14 (m, 1 H), 2.41–2.47 (m,
2 H), 2.85–2.92 (m, 1 H), 5.96 (d, J = 2.2 Hz, 1 H), 7.43 (t, J =
7.5 Hz, 1 H), 7.65 (t, J = 7.5 Hz, 1 H), 7.84 (d, J = 7.9 Hz, 1 H),
8.01 (d, J = 7.9 Hz, 1 H) ppm.
2-[Hydroxy(3-nitrophenyl)methyl]cyclohexanone
(21c):[12b,19,20]
Yield 95%; ratio anti/syn = 94:6. anti-Diastereomer (2S,1ЈR): 1H
NMR (300 MHz, CDCl3): δ = 1.30–1.85 (m, 6 H), 2.32–2.43 (m, 1
H), 2.48–2.53 (m, 1 H), 2.58–2.67 (m, 1 H), 4.13 (br. s, 1 H), 4.90
(d, J = 9.0 Hz, 1 H), 7.53 (t, J = 7.9 Hz, 1 H), 7.67 (d, J = 7.5 Hz,
1 H), 8.16 (d, J = 7.9 Hz, 1 H), 8.21 (d, J = 1.7 Hz, 1 H) ppm.
HPLC analysis Chiracel OD (hexane/iPrOH = 95:5; 1.5 mL/min;
220 nm; 20 °C) tR = 15.8 min (major) and tR = 21.9 min (minor);
er = 96:4; [α]D = +30.6 (c = 0.9, CHCl3). syn-Diastereomer: 1H
NMR (300 MHz, CDCl3): δ = 1.50–1.90 (m, 6 H), 2.39–2.52 (m, 2
H), 2.62–2.69 (m, 1 H), 3.23 (br. s, 1 H), 5.48 (s, 1 H), 7.52 (t, J =
7.9 Hz, 1 H), 7.67 (t, J = 7.5 Hz, 1 H), 8.12 (d, J = 8.3 Hz, 1 H),
8.19 (s, 1 H) ppm.
(CON), 174.2 (CON) ppm. IR (KBr): ν = 3313, 2976, 1651, 1538,
˜
1393, 1162, 1123, 753.1 cm–1. HRMS: calcd. for C20H29N3O4Na+
398.2056; found 398.2054.
(S)-N-[2-(4-Methylbenzamido)ethyl]pyrrolidine-2-carboxamide (20):
Obtained by reaction of 19 (1.31 g, 3.5 mmol) with TFA/CH2Cl2
(1:4) by the procedure described for the preparation of 5 and puri-
fied by flash column chromatography on silica gel (EtOAc/meth-
anol, 5:1); yield 0.77 g (2.8 mmol, 80%); colorless solid; m.p. 142–
143 °C (EtOAc); [α]2D3 = –65.4 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.64 (m, 2 H), 1.81 (m, 1 H), 2.09 (m, 2
2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone
Yield 95%; ratio anti/syn = 91:9. anti-Diastereomer (2S,1ЈR): 1H
(21d):[12b,18,19]
H), 2.36 (s, 3 H), 2.86 (dt, J = 10.1, 6.1 Hz, 1 H), 2.97 (dt, J = NMR (300 MHz, CDCl3): δ = 1.22–1.84 (m, 6 H), 2.30–2.41 (m, 1
10.1, 6.6 Hz, 1 H), 3.52 (m, 4 H), 3.72 (dd, J = 9.2, 5.3 Hz, 1 H), H), 2.46–2.63 (m, 2 H), 4.11 (d, J = 3.0 Hz, 1 H), 4.89 (dd, J =
7.20 (d, J = 8.2 Hz, 2 H), 7.57 (br. s, 1 H), 7.72 (d, J = 8.2 Hz, 2 8.3, 2.9 Hz, 1 H), 7.50 (d, J = 8.6 Hz, 2 H), 8.19 (d, J = 8.6 Hz, 2
H), 8.13 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.4
H) ppm. HPLC analysis Chiracel OD (hexane/iPrOH = 95:5;
(CH3), 26.1 (CH2), 30.8 (CH2), 38.7 (CH2), 41.7 (CH2), 47.2 (CH2), 1.0 mL/min; 220 nm; 20 °C) tR = 31.5 min (major) and tR
=
Eur. J. Org. Chem. 2010, 5310–5319
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5317

R. Pedrosa, J. M. Andrés, R. Manzano, P. Rodríguez
FULL PAPER
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46.3 min (minor); er = 97:3; [α]D = +10.9 (c = 0.5, CHCl3). syn-
Diastereomer: 1H NMR (CDCl3): δ = 1.52–2.12 (m, 6 H), 2.33–
2.50 (m, 2 H), 2.57–2.61 (m, 1 H), 3.20 (br. s, 1 H), 5.43 (s, 1 H),
7.43 (d, J = 8.0 Hz, 2 H), 7.63 (d, J = 8.3 Hz, 2 H) ppm.
2-[(4-Cyanophenyl)hydroxymethyl]cyclohexanone (21e):[18–20] Yield
1
[3]
[4]
[5]
98%; ratio anti/syn = 87:13. anti-Diastereomer (2S,1ЈR): H NMR
(300 MHz, CDCl3): δ = 1.35–2.14 (m, 6 H), 2.30–2.50 (m, 2 H),
2.53–2.61 (m, 1 H), 4.07 (br. s, 1 H), 4.83 (d, J = 8.8 Hz, 1 H), 7.45
(d, J = 8.3 Hz, 2 H), 7.65 (d, J = 8.3 Hz, 2 H) ppm. HPLC analysis
Chiracel OD (hexane/iPrOH = 95:5; 1.0 mL/min; 220 nm; 20 °C)
tR = 31.5 min (major) and tR = 46.3 min (minor); er = 95:5; [α]D
=
1
+17.7 (c = 0.9, CHCl3). syn-Diastereomer: H NMR (CDCl3): δ =
1.52–2.12 (m, 6 H), 2.33–2.50 (m, 2 H), 2.57–2.61 (m, 1 H), 3.20
(br. s, 1 H), 5.43 (s, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.63 (d, J =
8.3 Hz, 2 H) ppm.
2-[Hydroxy(phenyl)methyl]cyclohexanone (21f):[12b,18,19] Yield 81%;
ratio anti/syn = 94:6. anti-Diastereomer (2S,1ЈR): 1H NMR
(300 MHz, CDCl3): δ = 1.27–2.13 (m, 6 H), 2.31–2.52 (m, 2 H),
2.55–2.67 (m, 1 H), 3.99 (br. s, 1 H), 4.79 (d, J = 8.8 Hz, 1 H), 7.29–
7.40 (m, 5 H) ppm. HPLC analysis Chiracel OD (hexane/iPrOH =
90:10; 1.0 mL/min; 220 nm; 20 °C) tR = 9.6 min (major) and tR
=
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13.0 min (minor); er = 97:3; [α]D = +21.8 (c = 0.7, CHCl3). syn-
Diastereomer: 1H NMR (300 MHz, CDCl3): δ = 1.48–2.12 (m, 6
H), 2.33–2.48 (m, 2 H), 2.50–2.64 (m, 1 H), 3.05 (br. s, 1 H), 5.41
(s, 1 H), 7.25–7.41 (m, 5 H) ppm.
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2-[Hydroxy(4-methylphenyl)methyl]cyclohexanone (21g):[19,20] Yield
1
80%; ratio anti/syn = 91:9. anti-Diastereomer (2S,1ЈR): H NMR
(300 MHz, CDCl3): δ = 1.51–1.80 (m, 5 H), 2.05–2.11 (m, 1 H),
2.34 (s, 3 H), 2.41–2.50 (m, 2 H), 2.57–2.64 (m, 1 H), 3.94 (br. s, 1
H), 4.76 (d, J = 8.8 Hz, 1 H), 7.16 (d, J = 8.3 Hz, 2 H), 7.21 (d, J
= 8.3 Hz, 2 H) ppm. HPLC analysis Chiracel OD (hexane/iPrOH
= 95:5; 1.0 mL/min; 220 nm; 20 °C) tR = 12.2 min (major) and tR
= 16.2 min (minor); er = 96:4; [α]D = +22.3 (c = 0.7, CHCl3). syn-
Diastereomer: 1H NMR (300 MHz, CDCl3): δ = 1.48–1.88 (m, 5
H), 2.05–2.12 (m, 1 H), 2.35 (s, 3 H), 2.38–2.48 (m, 2 H), 2.55–2.62
(m, 1 H), 2.99 (br. s, 1 H), 5.36 (s, 1 H), 7.15 (d, J = 8.3 Hz, 2 H),
7.20 (d, J = 8.3 Hz, 2 H) ppm.
[8]
[9]
Supporting Information (see also the footnote on the first page of
this article): Synthesis of diamines 1 and 11, experimental pro-
cedures, spectroscopic data for new compounds and intermediates,
HPLC separation conditions and retention times for compounds
21a–g.
Acknowledgments
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Investigación Ciencia y Técnica (DGICYT) (Project CTQ2008-
03960/BQU) and Junta de Castilla y León (Project GR 168). R. M.
and P. R. also thank the Ministerio de Educación y Ciencia (MEC)
for a predoctoral fellowship (FPU).
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www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5310–5319

Bifunctional Organocatalysts for Selective Aldol Reactions
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8, 4417.
Received: May 3, 2010
Published Online: July 28, 2010
Eur. J. Org. Chem. 2010, 5310–5319
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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