Bisprolinediamides with the binaphthyl backbone as organocatalysts for the direct asymmetric aldol reaction

Article abstract of DOI:10.1055/s-2006-939701

A series of L-prolineamides derived from various aromatic diamines including 1,1′-binaphthyl-2,2′-diamine, were prepared in good yields. They were evaluated as catalysts for the direct asymmetric aldol reaction. The presence of the binaphthyl and proline

Full text of DOI:10.1055/s-2006-939701

LETTER
1059
Bisprolinediamides with the Binaphthyl Backbone as Organocatalysts for the
Direct Asymmetric Aldol Reaction
B
isprolinediamide
o
s
w
ith the Bi
r
naphthyl
o
Backbone
a
t
s
O
rgan
a
ocatalysts Gryko,*a Bartłomiej Kowalczyk,a,b Łukasz Zawadzkib
a
Institute of Organic Chemistry, Polish Academy of Science, Kasprzaka 44/52, 01-224 Warsaw, Poland
b
Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
Fax +48(22)6316681; E-mail: dgryko@icho.edu.pl
Received 17 January 2006
ee values were only obtained when these reactions were
performed at –35 °C.
Abstract: A series of L-prolineamides derived from various aro-
matic diamines including 1,1¢-binaphthyl-2,2¢-diamine, were pre-
pared in good yields. They were evaluated as catalysts for the direct
asymmetric aldol reaction. The presence of the binaphthyl and pro-
line moieties in one molecule has beneficial effects on the stereo-
chemical outcome of the reaction of acetone with a model aldehyde.
Furthermore, it was shown that dioxane as the solvent significantly
improved both yield and enantioselectivity, reaching 89% and 86%,
respectively.
Furthermore, Xiao et al.18 showed that the non-symmetric
bisamide derived from (1R,2R)-1,2-cyclohexanediamine,
L-proline, and 4-methylbenzoic acid is an effective cata-
lyst for the aldol reaction of cyclohexanone with aromatic
aldehydes giving products in good yield and up to 97% ee.
Since the catalysts are believed to stabilize the transition
state through hydrogen bonding to proline and its deriva-
tives, small changes in the catalyst structure might influ-
ence the strength of hydrogen bonding and as a result
change the selectivity of the reaction. It has also been
shown that variation of the electronic properties of the
acyl moiety on the catalyst could influence its activity and
selectivity.18
Key words: organocatalysis, aldol reaction, asymmetric synthesis,
binaphtyl, proline
Asymmetric catalysis has received considerable attention
over the past few decades and its contribution toward or-
ganic synthesis has become increasingly significant.1,2
A
With this in mind, we have synthesized bisprolinedi-
amides 4a–d derived from aromatic diamines (Scheme 1,
Figure 1). Diamines of type 2 were coupled with N-Boc-
L-proline 1 in the presence of Et3N and ethyl chlorofor-
mate,6b affording their respective N-protected bispro-
linediamides 3 in good yields; next they were treated with
TFA and Et3SiH19 giving pure 4a–d.
wide variety of enantioselective transformations can be
performed with catalytic amounts of a chiral promoter,
providing a highly economic access to optically active
compounds. All these catalytic transformations can fall
into one of three categories: transition metal catalysis, or-
ganocatalytic transformations, or enzymatic processes.
Over the past few years, rapid progress has been made in
the development of organocatalyzed processes.2,3 Since
the pioneering work by List et al.4 who demonstrated
L-proline itself can catalyze the intermolecular aldol
addition of acetone to 4-nitrobenzaldehyde, with fair
enantioselectivities, proline itself has become a very
attractive catalyst but its catalytic activity can be fine-
tuned only by changing the reaction conditions. Since
that time several proline-derived catalysts have been
prepared.5–16
Newly prepared catalysts 4a–d were tested in the model
aldol reaction of acetone with 4-nitrobenzaldehyde (6a).
R
+
CO2H
H2N
NH2
N
Boc
1
2a–f
Et3N
EtOCOCl
Recently, the simplest C2-symmetric bisamide derived
from L-proline and ethylenediamine showed very high ac-
tivity but low stereoselectivity in the model aldol reac-
tion.17 The use of (1S,2S)-1,2-diphenylethylenediamine as
a linkage improved the selectivity of the catalyst apprecia-
bly. The stereoselectivity of the aldol reaction catalyzed
by C2-symmetric bisprolinediamides were strongly influ-
enced by the nature of the linkage. Though this work is el-
egant it has one major drawback, the reaction conditions
vary from case to case (anhydrous acetone, CH2Cl2 for cy-
clopentanone, and THF for 2-hydroxyacetone) and good
R
O
O
NH
HN
3a–f
NBoc
BocN
TFA, Et3SiH
CH2Cl2
R
O
O
NH
NH
HN
4a–f
HN
SYNLETT 2006, No. 7, pp 1059–1062
0
3.
0
5.
2
0
0
6
Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939701; Art ID: G01306ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Synthesis of bisprolinediamides of type 4

1060
D. Gryko et al.
LETTER
O
O
O
O
O
O
O
O
NH HN
N
N
N
N
H
H
N
HN
NH
N
N
H
NH
HN
H
H
H
HN
NH
NH
HN
4a
4b
4c
4d
O
O
O
O
N
N
N
N
NH
HN
HN
HN
NH
HN
Ph
H
H
H
H
NH
O
NH
O
NH
O
NH
O
Ph
4e
4f
5a
5b
Figure 1 Bisprolinediamides 4 and 5 used as catalysts for the model aldol reaction of acetone with 4-nitrobenzaldehyde 6a
The structure of the aromatic amine moiety had a small ef- Maruoka et al.13 have recently described a new axially
fect on the yield of 7a, yields were usually in the range chiral amino acid with a binaphthyl backbone, which has
50–70%. The reaction catalyzed by diamide 4b gave the found application as a catalyst in the aldol reaction. The
lowest yield and moderate ee (Table 1, entry 2). When yields as well as the enantiomeric excesses for the model
2,6-diaminopyridine was used as a linkage (catalyst 4d) reaction of 4-nitrobenzaldehyde (6a) with acetone were
the yield of 7 increased to 67% (Table 1, entry 4). The higher than those reported for the proline-catalyzed reac-
presence of an electron-withdrawing group (pyridine moi- tion. Thus, we prepared new organocatalysts 4e and 4f
ety) in place of the phenyl substituent enhanced the acidi- which have the 1,1¢-binaphthyl-2,2¢-diamine 2 and L-pro-
ty of the amide proton, thus, the reactivity of the catalyst line joined, such that the organocatalyst possesses axial
was higher. Also, since the ee remained unchanged, we chirality. We designed our new catalyst in such a way that
assumed that the nitrogen atom did not participate in the we could benefit from the profitable influence of both the
transition state.
binaphthyl backbone and the proline moiety. The obvious
way in doing so was to utilize the approach described by
Jurczak et al.20 for the synthesis of 1,1¢-binaphthyl-2,2¢-
diamides derived from natural amino acids. Thus racemic
1,1¢-binaphthyl-2,2¢-diamine 2 was coupled with N-Boc-
L-proline 16b affording a mixture of diastereoisomeric
products 3 (Scheme 1). After separation by column chro-
matography on silica gel and deprotection of the Boc-
group,19 pure products 4e and 4f were obtained.21 It should
be pointed out that these two optically pure catalyst were
obtained from cheap, racemic diamine 2. Both were used
as catalysts for the model aldol reaction of 4-nitrobenzal-
dehyde (6a) with acetone (Table 1). We were delighted to
discover that both reactions gave good yields (Table 1, en-
tries 5, 6), as well as improved enantioselectivity when the
reaction was carried out in dioxane. The catalyst 4e af-
forded a superior level of stereocontrol to its diastereoiso-
mer 4f. This indicates that the S configuration of the
binaphthyl moiety matches the L-proline, enhancing the
stereoselectivity, whereas in the other case, the two frag-
ments form a mismatched pair (catalyst 4f).
The binaphthyl backbone has been widely used in transi-
tion-metal catalysis and is believed to be the factor, which
determines the effectiveness of the catalyst. In addition,
Table 1 The Aldol Addition of Acetone to 4-Nitrobenzaldehydea
OH
O
CHO
O
cat.
+
4 °C, 68 h
O2N
O2N
7a
6a
Acetone
Yield (%)b ee (%)c
Dioxane
Yield (%)b ee (%)c
Entry
Catalyst
4a
1
2
3
4
5
6
7
8
72
48
57
67
69
70
51
70
43
51
41
51
65
32
40
83
–
–
4b
–
–
4c
–
–
4d
–
–
4e
89
–
86
–
The strength of hydrogen bonding might influence the cat-
alytic properties of the catalyst since it is believed that the
transition state in proline and its derivative is stabilized
through hydrogen bonding. Xiao et al.18 have also shown
that the activity and selectivity of the catalyst can be tuned
by changing one of the acyl moieties in the bisprolinedi-
amides catalyst. With this in mind we have synthesized
catalysts 5a and 5b possessing only one proline moiety.22
The reaction of (S)- or (R)-1,1¢-binaphthyl-2,2¢-diamine
with an equimolar amount of N-Boc-L-proline gave the
4f
5a
80
73
84
74
5b
a Reagents and conditions: 4-nitrobenzaldehyde (1 mmol), acetone (2
mL), catalyst (0.1 mmol), 4 °C, 68 h.
b Isolated yields.
c Determined by HPLC using an ASH column.
Synlett 2006, No. 7, 1059–1062 © Thieme Stuttgart · New York

LETTER
Bisprolinediamides with the Binaphthyl Backbone as Organocatalysts
1061
respective monoprolineamide in 43% yield. Subsequent In conclusion, we have synthesized new chiral organocat-
reaction with benzoylchloride followed by treatment with alysts, which connect an axially chiral binaphthyl back-
TFA and Et3SiH19 yielded bisamides 5a and 5b. When bone with the centrally chiral proline moiety. The highly
compound 5a catalyzed the reaction of acetone with 4-ni- skewed position of the naphtyl rings influences the cata-
trobenzaldehyde (6a) the yield as well as the ee dropped lytic activity of the proline moiety. The S configuration of
substantially compared with 4e (Table 1, entry 7). On the the binaphthyl moiety matches the S configuration of the
other hand its diastereoisomer 5b afforded superior levels proline in symmetric catalysts 4e and 4f. Additionally, it
of stereocontrol (Table 1, entry 8). When the reactions was shown that the replacement of the binaphthyl moiety
were carried out in dioxane the enantioselectivity in- with other aromatic diamines in the diamide catalysts 4
creased or remained at the same level. Since the results causes a decrease in the enantioselectivity. Our studies
obtained in acetone and dioxane are contradictory, we have shown that to obtain efficient catalysis a certain con-
cannot clearly state which configuration of the binaphtyl formation is required since the structure of the linkage in-
backbone matches the S configuration of proline.
fluences the enantioselectivity of the model aldol reaction.
We believe that the dihedral angle between both proline
moieties is the determining factor. Furthermore the use of
dioxane as a solvent for the direct asymmetric aldol reac-
tion catalyzed by 4e not only improved the yield and the
stereochemical outcome of the reaction but also allowed
the use of other donors. The aldol reaction of acetone with
various aryl aldehydes 6 afforded aldols with moderate to
good yield and fair enantioselectivities.
The scope of the aldol reaction using symmetric catalyst
4e was examined with a series of aryl aldehydes 6b–j
(Table 2) and ketone donors (Scheme 2). In most cases
good yields and fair enantioselectivities were obtained.
Unfortunately, reactions of 4-nitrobenzaldehyde (6a) with
cyclopentanone (8) and cyclohexanone (9) afforded aldols
10 and 11, respectively, with moderate diastereoselectivi-
ty and low enantioselectivity.
Our work underlines how difficult the rational design of
efficient catalysts is and how much work is still needed.
Table 2 Bisprolinediamide 4e catalyzed aldol reactiona
Entry
R
Product
7b
Yield (%)b
ee (%)c
71
Acknowledgment
1
2
3
4
5
6
7
8
9
C6F5
79
74
72
75
73
53
16
15
9
We thank Prof. J. Jurczak for helpful discussions.
4-CN-C6H4
4-CF3-C6H4
2,6-Cl2-C6H3
2-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
C6H5
7c
73
7d
88
References and Notes
7e
85
(1) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive
Asymmetric Catalysis; Springer-Verlag: Berlin, Heidelberg,
1999.
(2) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis;
Wiley-VCH: Weinheim, 2005.
(3) (a) List, B. Tetrahedron 2002, 58, 5573. (b) Dalko, P. I.;
Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138.
(c) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570.
(d) Notz, W.; Tanaka, F.; Barbas, C. F. III Acc. Chem. Res.
2004, 37, 580.
7f
62
7g
77
7h
54
7i
74
b-naphtyl
7j
50
(4) List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc.
2000, 122, 2395.
(5) (a) Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry
2004, 15, 1831. (b) Hartikka, A.; Arvidsson, P. I. Eur. J.
Org. Chem. 2005, 4287.
a All reactions were performed with 1 mmol of aldehyde, 1 mL of
acetone, 4 mL of dioxane and 0.1 mmol of catalyst at 4 °C for 68 h.
b Isolated yields.
c Determined by HPLC using ASH or ADH column.
(6) (a) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.; Mi,
A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125,
5262. (b) Tang, Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-
Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5755. (c) Tang, Z.; Yang, Z.-H.; Chen, X.-H.;
Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am.
Chem. Soc. 2005, 127, 9285.
(7) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245.
(8) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.;
Urushima, T.; Shoji, M.; Hashizume, D.; Koshino, H. Adv.
Synth. Catal. 2004, 346, 1435.
OH
O
O
CHO
cat.
+
4 °C, 68 h
( )n
( )n
O2N
O2N
6a
8 n = 1
9 n = 2
n = 1
syn-10:anti-10
74 (17% ee):26 (45% ee)
syn-11:anti-11
n = 2
30 (8% ee):70 (47% ee)
Scheme 2 Aldol reactions of aldehyde 6a with cyclic ketones
(9) Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004,
346, 1141.
(10) Zou, W.; Ibrahem, I.; Dziedzic, P.; Sundén Córdova, A.
Chem. Commun. 2005, 4946.
(11) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.;
Ley, S. V. Org. Biomol. Chem. 2005, 3, 84.
Further work on optimizing the reaction conditions as
well as on the properties of the catalyst are currently
underway.
(12) Gryko, D.; Lipiński, R. Adv. Synth. Catal. 2005, 347, 1948.
Synlett 2006, No. 7, 1059–1062 © Thieme Stuttgart · New York

1062
D. Gryko et al.
LETTER
(13) Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew. Chem.
Int. Ed. 2005, 44, 3055.
(14) Bellis, E.; Kokotos, G. Tetrahedron 2005, 61, 8669.
(15) Cheng, C.; Sun, J.; Wang, C.; Zhang, Y.; Wei, S.; Jiang, F.;
Wu, Y. Chem. Commun. 2006, 215.
(16) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F. I. I. I. J. Am. Chem. Soc. 2006, 734.
(17) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C.-G. Org. Lett. 2005,
7, 5321.
of (R)-1,1¢-binaphthyl-2,2¢-diamine (0.57 g, 2 mmol) was
added dropwise over 5 min at 0 °C. The reaction was stirred
overnight at r.t. and the white precipitate (Et3N·HCl) formed
was removed by filtration. The filtrate was concentrated in
vacuo, and the residue was purified by column chromatog-
raphy (n-hexane–EtOAc, ca. 4:1) to yield (S)-tert-butyl 2-
[(R)-1-(2-aminonaphthalen-1-yl)naphthalene-2-yl-
carbamoyl]pyrrolidine-1-carboxylate (0.42 g, 0.87 mmol,
44%).
(18) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.; Xiao,
W.-J. Org. Lett. 2005, 7, 4543.
(19) Mehta, A.; Jaouhari, R.; Benson, T. J.; Douglas, K. T.
Tetrahedron Lett. 1992, 33, 5441.
(20) Kowalczyk, B.; Tarnowska, A.; Weseliński, Ł.; Jurczak, J.
Synlett 2005, 2373.
To a solution of (S)-tert-butyl 2-[(R)-1-(2-aminonaphthalen-
1-yl)naphthalene-2-yl-carbamoyl]pyrrolidine-1-carboxylate
(175 mg, 0.36 mmol) in anhyd THF (5 mL), Et3N (50 mL,
0.36 mmol) was added and the resulting mixture was cooled
to 0 °C. Then benzoyl chloride (45mL, 0.36 mmol) was
added dropwise, the mixture was stirred for 2 h, and the
white precipitate (Et3N·HCl) was removed by filtration. The
filtrate was concentrated in vacuo and then the residue was
purified by column chromatography (n-hexane–EtOAc, 7:3)
to give (S)-tert-butyl 2-[(R)-1-(2-benzamido)naphthalene-1-
yl]naphthalene-2-yl-carbamoylpyrrolidine-1-carboxylate
(198 mg, 0.34 mmol) in 94% yield.
To a solution of (S)-tert-butyl 2-[(R)-1-(2-benzamido)naph-
thalene-1-yl]naphthalene-2-yl-carbamoyl-pyrrolidine-1-
carboxylate (198 mg, 0.34 mmol) in CH2Cl2 (680 mL),
excess TFA (340 mL), and Et3SiCl (45 mL) was added. The
resulting mixture was stirred for 2 h at r.t. The volatile
compounds were removed and the pH of the residue was
adjusted to <7 by the addition of a sat. aq solution of
NaHCO3, the product was extracted with CH2Cl2, and dried
over MgSO4. The solvent was removed to give pure 5b (160
mg, 0.33 mmol, 97%). Mp 80–82 °C; [a]D25 +10.9 (c 0.80,
CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 9.70 (1 H, s),
8.80 (1 H, AB/2, J = 9.0 Hz), 8.55 (1 H, AB/2, J = 9.0 Hz),
8.09 (1 H, AB/2, J = 9.1 Hz), 8.08 (1 H, AB/2, J = 9.1 Hz),
7.95 (2 H, dd, J = 3.8, 8.1 Hz), 7.86 (1 H, br s), 7.68–7.11
(11 H, m), 3.58 (1 H, dd, J = 4.4, 9.4 Hz), 2.57 (1 H, dt, J =
9.9, 7.2 Hz), 1.90–1.82 (1 H, m), 1.59 (1 H, ddt, J = 12.5,
7.2, 4.9 Hz), 1.44–1.36 (1 H, m), 1.26 (1 H, s), 1.15 (1 H, dq,
J = 20.0, 7.3 Hz). 13C NMR (125 MHz, CDCl3): d = 174.1,
165.4, 135.2, 135.0, 134.4, 132.6, 132.5, 131.7, 131.2,
131.1, 130.2, 130.0, 128.6, 128.3, 128.2, 127.5, 127.1,
126.7, 125.6, 125.23, 125.19, 125.1, 121.2, 120.8, 60.6,
46.6, 30.5, 25.6. HRMS (ESI): m/z calcd for C32H28N3O2:
486.2176; found: 486.2171.
(21) Compounds of Type 4; Typical Procedure
To a solution of N-Boc protected proline 1 (4.3 g, 20.0
mmol) in anhyd THF (50 mL), Et3N (2.8 mL, 20.1 mmol)
was added and the mixture was cooled to 0 °C, then ethyl
chloroformate (2.5 mL, 20 mmol) was added dropwise over
15 min. The reaction temperature was maintained at 0 °C for
30 min, then a THF (10 mL) solution of racemic 1,1¢-bi-
naphthyl-2,2¢-diamine (2.84 g, 10 mmol) was added drop-
wise over 15 min at 0 °C. The reaction mixture was stirred
overnight and then refluxed for 4 h. Finally, after cooling to
r.t., the white precipitate (Et3N·HCl) was removed by
filtration, and the filtrate was concentrated in vacuo. Then
the residue was purified by column chromatography (n-
hexane–EtOAc, ca 4:1) to give two diastereomeric products
3e (2.41 g, 3.6 mmol) and 3f (2.46 g, 3.7 mmol) in 73%
overall yield. To a solution of diamide 3e (0.75 g, 1.1 mmol)
in CH2Cl2 (3 mL), excess TFA (1.5 mL), and Et3SiCl (1.5
mL) was added and the resulting mixture was stirred for 2 h
at r.t. The solvent was removed and the pH of the residue was
adjusted to <7 by the addition of an aq sat. solution of
NaHCO3, the product was extracted with CH2Cl2, and dried
over MgSO4. Removal of the solvent resulted in pure 4e
(0.45 g, 0.94 mmol, 85%).
4e Mp 203–208 °C (dec.); [a]D25 –142.8 (c 0.94, CH2Cl2). 1H
NMR (200 MHz, CDCl3): d = 9.70 (1 H, s), 8.82 (2 H, AB/
2, J = 9.0 Hz), 8.04 (2 H, AB/2, J = 9.0 Hz), 7.44–7.15 (6 H,
m), 3.62 (2 H, dd, J = 9.3, 4.4 Hz), 2.40 (2 H, ddd, J = 9.6,
6.6, 7.8 Hz), 1.96 (4 H, m), 1.57 (2 H, br s), 1.45 (2 H, ddd,
J = 6.6, 9.8, 4.8 Hz), 1.35–1.17 (2 H, m), 0.98–0.77 (2 H, m).
13C NMR (50 MHz, CDCl3): d = 174.0, 135.2, 132.5, 130.9,
129.6, 128.2, 126.9, 125.0, 124.9, 119.7, 119.2, 60.6, 46.2,
30.7, 25.4. HRMS (ESI): m/z calcd for C30H31N4O2:
479.2442; found: 479.2458.
Aldol Reaction; General Procedure
To a stirred solution of a catalyst (0.1 mmol) in dioxane (4
mL) at 0 °C, acetone (1 mL) (or other ketones) and an
aldehyde 6 (1 mmol) were added under air in a closed
system. The reaction mixture was stirred at 4 °C for 68 h.
Then the reaction mixture was diluted with EtOAc and
washed with a sat. aq solution of NH4Cl. The organic layer
was separated and dried over Na2SO4. Column
(22) Compounds of Type 5; Typical Procedure
To a solution of N-Boc protected proline 1 (0.43 g, 2 mmol)
in anhyd THF (5 mL), Et3N (0.24 mL, 2 mmol) was added
and the mixture was cooled to 0 °C with stirring, then ethyl
chloroformate (0.18 mL, 1.5 mmol) was added dropwise
over 15 min. After the addition the reaction temperature was
maintained at 0 °C for 30 min. Then a THF solution (1 mL)
chromatography (silica gel, hexanes–EtOAc) gave pure
aldol 7.
Synlett 2006, No. 7, 1059–1062 © Thieme Stuttgart · New York