trans-4-hydroxy-L-proline hydrazide-trifluoroacetic acid as highly stereoselective organocatalyst for the asymmetric direct aldol reaction of cyclohexanone

Article abstract of DOI:10.1055/s-2006-950431

Protonated N′-benzyl-N′-L-prolyl-trans-4-hydroxy-L-proline hydrazide has been found to be superior to the L-proline hydrazide counterpart as the catalyst for the asymmetric aldol reaction of cyclohexanone and aromatic aldehydes, resulting in excellent dia

Full text of DOI:10.1055/s-2006-950431

LETTER
2419
trans-4-Hydroxy-L-proline Hydrazide–Trifluoroacetic Acid as Highly
Stereoselective Organocatalyst for the Asymmetric Direct Aldol Reaction of
Cyclohexanone
cid ling Cheng,a,b Siyu Wei, Jian Sun*a
a
t
C
rans-4-Hydroxy
h
L
-proline Hy
u
drazide–Tri
a
nA
a
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Fax +86(28)85222753; E-mail: sunjian@cib.ac.cn
b
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Received 20 June 2006
lyst 1, the pyrrolidinyl group closer to the hydrazide NH
on the left) plays the central role in the enamine forma-
tion in the course of the aldol reaction, whereas the other
pyrrolidinyl group (on the right) mainly functions as a
Abstract: Protonated N¢-benzyl-N¢-L-prolyl-trans-4-hydroxy-L-pro-
line hydrazide has been found to be superior to the L-proline hy-
drazide counterpart as the catalyst for the asymmetric aldol reaction
of cyclohexanone and aromatic aldehydes, resulting in excellent
(
diastereoselectivities (up to >99:1 dr) and enantioselectivities (up to hydrogen-bond donor, upon protonation, to facilitate the
99% ee).
formation of the hydrogen-bonding network in the transi-
Key words: proline hydrazide, enantioselectivity, diastereoselec- tion state of the nucleophilic addition of the enamine to
>
tivity, cyclohexanone, asymmetric direct aldol reaction
the aldehyde (see the structures of the protonated species
inside the bracket in Figure 1). We speculated that the in-
5
troduction of a trans-4-substituent on C4 and C4¢ might
The asymmetric direct aldol reaction is one of the most have different influences on the efficiency of the catalyst.
powerful C–C bond-forming reactions for the production Thus catalysts 2-4 (Figure 1) with a trans-hydroxyl
1
of chiral 1,3-dioxygenated compounds. The development group on C4 and/or C4¢ were prepared starting from the
of novel chiral organocatalyts for this transformation has easily accessible trans-4-hydroxy-L-proline and/or L-
2
8,9
recently been the subject of intense research since List, proline and tested in the model aldol reaction of p-nitro-
benzaldehyde and cyclohexanone (Scheme 1).
Barbas and Lerner reported that L-proline could effective-
ly catalyze the intermolecular direct aldol reaction. A
number of proline derivatives have emerged as highly ef-
ficient and stereoselective catalysts. In our previous re-
port, we presented the first proline hydrazide, N¢-benzyl-
N¢-L-prolyl-L-proline hydrazide (1; Figure 1) that, upon
protonation with trifluoroacetic acid (TFA), behaved as a
highly efficient and enantioselective catalyst in the aldol
reaction of aromatic aldehydes and acetone. This catalyst
was also shown to efficiently catalyze the aldol reaction
3
Ph
Ph
O
O
4
N
O
N
O
R1
N
R1
N
4
H
H
NH
NH
CF3CO2–
H
HN
N
4'
H
R2
R2
5
1
1
2
2 R = H, R2 = OH
1
1
3
R
R
= R = H
= R = OH 4 R = OH, R2 = H
2
1
between cyclohexanone (5) and p-nitrobenzaldehyde (6a;
Scheme 1). However, the resulting diastereomeric ratios Figure 1
92:8 for the anti/syn products) and ee values (92% for the
(
major anti isomer) are not excellent. Herein, we report
that the analogous N¢-benzyl-N¢-L-prolyl-trans-4-hy-
droxy-L-proline hydrazide (4; Figure 1) proved to be a
superior catalyst for the aldol reaction of cyclohexanone
O
O
OH
O
OH
O
catalyst,
TFA
H
+
Ar
Ar
+
toluene,
0 °C
O2N
6
and aromatic aldehydes, affording products in up to
6a
5
anti-7a
syn-7a
>99:1 dr and >99% ee.
Scheme 1
Introduction of a trans-4-substituent, if appropriate, to the
pyrrolidinyl backbone has recently proven to have some
positive and profound impacts on the catalytic effects of
the proline-based organocatalysts.3b,4n,7 We were interest-
ed to investigate if there exists any such effect with the
proline hydrazide catalyst system. Our previous studies
have demonstrated that in the molecular structure of cata-
As illustrated in Table 1, catalysts 2-4 all exhibited sig-
nificantly improved reactivity compared with the parent
catalyst 1 (entries 4-6 vs entry 3), furnishing products
with >90% yield in one hour. While 2 gave slightly de-
creased dr and ee values, 3 afforded a slightly improved dr
and a significantly enhanced ee value. The best diastereo-
selectivity (99:1 dr for the anti/syn isomers) and enantio-
selectivity (98% ee for the major anti isomer) were
obtained with 4. These results clearly indicate that the ex-
istence of the trans-hydroxyl group on C4 is beneficial to
SYNLETT 2006, No. 15, pp 2419–2422
1
8
.0
9
.2
0
0
6
Advanced online publication: 08.09.2006
DOI: 10.1055/s-2006-950431; Art ID: W11906ST
©
Georg Thieme Verlag Stuttgart · New York

2
420
C. Cheng et al.
LETTER
Table 1 Asymmetric Direct Aldol Reaction of 4-Nitrobenzaldehyde (6a) with Cyclohexanone (5) under Various Conditionsa
Entry
Catalyst
C [M]
0.2
Molar ratio (5/6a) Time (h)
Yield (%)b
dr (anti/syn)c
92:8
ee (%, anti)d
1
2
3
4
5
6
7
1
1
1
2
3
4
4
4
20
10
10
10
10
10
5
24
24
1
98
96
73
94
99
99
51
94
92
93
86
84
95
98
95
98
0.2
98:2
0.5
97:3
0.5
1
95:5
0.5
1
98:2
0.5
1
99:1
0.5
1
98:2
8
0.2
10
5
99:1
a
Unless specified otherwise, the reaction was carried out with catalyst (20 mol%) and TFA (20 mol%) in toluene at 0 °C.
Isolated yield based on the aldehyde.
Determined by chiral HPLC analysis of the mixture of the anti/syn product.
Determined by chiral HPLC.
b
c
d
the reactivity, diastereoselectivity and enantioselectivity (entries 7-10), which, however, afforded low to moderate
of the catalyst for the model aldol reaction, whereas the yields due to their attenuated reactivities. Not unsurpris-
same group on C4¢ only benefits the reactivity and has lit- ingly, the heteroaromatic aldehydes 6k-p also proved to
tle impacts on diastereoselectivity and enantioselectivity. be good substrates. In particular, the nitrogen-containing
heteroaromatic aldehydes 6l-p reacted well to give the
We further investigated the influences of other reaction
corresponding aldol products in high diastereoselectivity
parameters on the performance of the most efficient cata-
and enantioselectivity (up to 99:1 dr and 99% ee, entries
lyst 4 in the model reaction. Decreasing the molar ratio of
cyclohexanone (5) to aldehyde 6a from ten to five led to a
much slower reaction rate (99% vs 51% yield, entry 6 vs
1
2-16). These substrates, which could be problematic be-
cause the strong basicity of the nitrogen atom(s) could
disturb the acid–base bifunctional catalysis, have rarely
been used for the asymmetric organocatalytic aldol reac-
tion.4n Notably, catalyst 4 proved to be ineffective for
aliphatic aldehydes, for example, giving less than 10%
conversion for isobutyraldehyde after one week.
7
9
, Table 1) and a decreased enantioselectivity (98% vs
5% ee) with an almost unchanged diastereoselectivity
(
99:1 vs 98:2 dr). Lowering the concentration of the reac-
tion from 0.5 M to 0.2 M only slowed down the reaction
to some degree (entry 6 vs 8), but had no effect on the dr
and ee values.
In summary, we have demonstrated that N¢-benzyl-N¢-L-
prolyl-trans-4-hydroxy-L-proline hydrazide (4) is a supe-
rior catalyst compared to the parent L-proline hydrazide
counterpart 1 for the asymmetric direct aldol reaction of
cyclohexanone with aromatic aldehydes. In the presence
of this catalyst, excellent diastereoselectivities (up to
O
OH
O
OH
O
O
2
0 mol% 4, TFA
R
R
+
+
H
R
toluene, 0 °C
6
5
anti-7
syn-7
>
99:1 dr) and enantioselectivities (>99% ee) were ob-
tained for a broad range of aromatic aldehydes, including
heteroaromatic aldehydes. For comparisons to the other
organocatalysts, the remarkable features of this catalyst
Scheme 2
6
Having established the optimal reaction conditions, we
next probed the general applicability of catalyst 4.10
include: the high reactivity and the excellent diastereo-
selectivity and enantioselectivity, the requirement of the
use of non-polar toluene as the solvent and the mild reac-
tion conditions. Further studies focusing on the mechanis-
A
range of aromatic aldehydes 6a-p were reacted with
cyclohexanone in the presence of 20 mol% catalyst and an
equal amount of TFA in toluene at 0 °C (Scheme 2).
Table 2 summarizes the results. The reactions of benzal-
dehydes 6a-f bearing an electron-withdrawing group on
the benzene ring proceeded smoothly to furnish the aldol
products in high yield (up to 99%, entries 1–6) and excel-
11
tic aspects and the full application scope of this catalyst
system are currently underway and will be reported in due
course.
lent diastereoselectivity (up to >99:1 dr for the anti/syn Acknowledgment
isomers) and enantioselectivity (up to >99% ee for the
major anti isomer). High dr and ee values were also ob-
tained with the relatively electron-rich aldehydes 6g-j Chinese Academy of Sciences (Hundred of Talents Program).
We are grateful for financial supports from National Natural
Science Foundation of China (Project 20402014) and from the
Synlett 2006, No. 15, 2419–2422 © Thieme Stuttgart · New York

LETTER
trans-4-Hydroxy-L-proline Hydrazide–Trifluoroacetic Acid
2421
Table 2 Scope of the Aldehyde 6 for the Aldol Reaction with
Cyclohexanone (5) Catalyzed by 4
Chem. Int. Ed. 2004, 43, 1983. (e) Halland, N.; Braunton,
A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J. Am.
Chem. Soc. 2004, 126, 4790. (f) Berkessel, A.; Koch, B.;
Lex, J. Adv. Synth. Catal. 2004, 346, 1141. (g) 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.
(h) Krattiger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.;
Wennemers, H. Org. Lett. 2005, 7, 1101. (i) Chen, J.; Lu,
H.; Li, X.; Cheng, L.; Wan, J.; Xiao, W. Org. Lett. 2005, 7,
Entry Aldehyde
Time
Yield
(%)
dr
ee
b
c
d
(
h)
(anti/syn) (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
4-NO C H (6a)
1
99
99
96
93
93
90
84
55
39
69
69
93
95
74
78
99:1
>99:1
98:2
98:2
99:1
99:1
94:6
98:2
96:4
95:5
99:1
97:3
99:1
89:11
97:3
98
2
6
4
3-NO C H (6b)
3
>99
98
97
97
96
92
94
93
95
97
97
99
97
94
2
6
4
4543. (j) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C. Org. Lett.
2-NO C H (6c)
5
2
6
4
2005, 7, 5321. (k) Wang, W.; Li, H.; Wang, J. Tetrahedron
4-CNC H (6d)
4
Lett. 2005, 46, 5077. (l) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol.
Chem. 2005, 3, 84. (m) Tang, Z.; Cun, L. F.; Cui, X.; Mi, A.
Q.; Jiang, Y. Z.; Gong, L. Z. Org. Lett. 2006, 8, 1263.
6
4
4-ClC H (6e)
72
72
72
72
72
72
72
1
6
4
4-BrC H (6f)
6
4
(
n) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.;
Urushima, T.; Shoji, M. Angew. Chem. Int. Ed. 2005, 44,
58. (o) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe,
K.; Tanaka, F.; Barbas, C. F. III J. Am. Chem. Soc. 2006,
28, 734.
Ph (6g)
9
4-MeC H (6h)
6
4
1
4-OMeC H (6i)
6
4
(5) Cheng, C.; Sun, J.; Wang, C.; Zhang, Y.; Wei, S.; Jiang, F.;
Wu, Y.-D. Chem. Commun. 2006, 215.
1
1
1
1
1
1
1-Naphthyl (6j)
2-Furfuryl (6k)
4-Py (6l)
(
6) For the currently available highly diastereoselective and
enantioselective organocatalysts for the same reactions, see
references 4i, 4n, 4o. See also: (a) Cordova, A.; Zhou, W.;
Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W. Chem.
Commun. 2005, 3586. (b) Zhou, W.; Ibrahem, I.; Dziedic,
P.; Sunden, H.; Cordova, A. Chem. Commun. 2005, 4946.
3-Py (6m)
3
(c) Wu, Y.; Chen, Y.; Deng, D.; Cai, J. Synlett 2005, 1627.
2-Py (6n)
4
(
7) (a) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.;
Urushima, T.; Shoji, M.; Hashizume, D.; Koshino, H. Adv.
Synth. Catal. 2004, 346, 1435. (b) Bellis, E.; Kokotos, G.
Tetrahedron 2005, 61, 8669. (c) Casas, J.; Engqvist, M.;
Ibrahem, I.; Kaynak, B.; Cordova, A. Angew. Chem. Int. Ed.
4
N
N
2
005, 44, 1343.
(
(
6o)
6p)
(
8) General Procedure for the Preparation of Catalysts 2-4:
16
48
74
97:3
96
N
S
To a solution of Boc-L-Pro-NHNH (for 2) or trans-4-(tert-
butyldimethylsilyloxy)-Boc-L-Pro-NHNH (for 3 and 4; 8.0
mmol) in toluene (20 mL) was added benzaldehyde (935 mg,
2
2
8.8 mmol). The reaction mixture was stirred at r.t. for 24 h,
a
and then concentrated under reduced pressure. The residue
was dissolved in MeOH (80 mL), and 5% Pd/C (0.2 g) was
added. After stirring under hydrogen (1 atm) for 1 h, the
reaction mixture was filtered. The filtrate was concentrated
under reduced pressure. The residue was purified through
column chromatography on silica gel (eluent: PE-EtOAc,
The reaction was carried out with catalyst 4 (20 mol%) and TFA
20 mol%) in toluene at 0 °C.
Isolated yield based on the aldehyde.
Determined by chiral HPLC analysis of the mixture of the anti/syn
(
b
c
product.
d
For the major anti isomer, determined by chiral HPLC.
3:1) to give N¢-benzyl-Boc-L-proline hydrazide or N¢-
benzyl-trans-4-(tert-butyldimethylsilyloxy)-Boc-L-proline
hydrazide.
To a solution of N¢-benzyl-Boc-L-proline hydrazide or N¢-
benzyl-trans-4-(tert-butyldimethylsilyloxy)-Boc-L-proline
hydrazide (2.0 mmol) in DMF (20 mL) were added Boc-L-
Pro (for 4) or trans-4-hydroxy-Boc-L-Pro (for 2 and 3; 2.4
mmol), N,N-diisopropylethylamine (DIPEA, 700 mL) and
HATU (922 mg, 2.4 mmol) at 0 °C. The reaction mixture
was stirred at r.t. for 24 h, and then concentrated under
reduced pressure. The residue was dissolved in EtOAc. The
References and Notes
(
(
(
1) (a) Modern Aldol Reactions, Vol. 1; Mahrwarld, R., Ed.;
Wiley-VCH: Weinheim, 2004. (b) Modern Aldol Reactions,
Vol. 2; Mahrwarld, R., Ed.; Wiley-VCH: Weinheim, 2004.
2) For recent reviews, see: (a) Palomo, C.; Oiarbide, M.;
Garcia, J. M. Chem. Soc. Rev. 2004, 33, 65. (b) Saito, S.;
Yamamoto, H. Acc. Chem. Res. 2004, 37, 570.
3) (a) List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc.
organic phase was then washed with sat. aq NaHCO and
3
2
000, 122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.;
Barbas, C. F. III J. Am. Chem. Soc. 2001, 123, 5260.
c) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
brine and dried over anhyd Na SO . After removal of solvent
2
4
under reduced pressure, the residue was purified through
column chromatography on silica gel (eluent: PE-EtOAc,
(
(
4) For selected examples, see: (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.; Yang, Z.
H.; Cun, L. F.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. Org. Lett.
2:1) to give a white solid, which was then treated with a
mixture of TFA-CH Cl (1:2, 20 mL). After stirring at r.t.
2
2
for 1 h, the reaction mixture was concentrated under reduced
pressure. The residue was subjected to chromatography on a
2004, 6, 2285. (c) Mase, N.; Tanaka, F.; Barbas, C. F. III
+
H ion-exchange resin column with NH ·H O (3.0 M) as
3
2
Angew. Chem. Int. Ed. 2004, 43, 2420. (d) Torii, H.;
Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew.
eluent to give a crude product, which was further purified
Synlett 2006, No. 15, 2419–2422 © Thieme Stuttgart · New York

2
422
C. Cheng et al.
LETTER
through column chromatography on silica gel (eluent:
(10) Typical Procedure for the Aldol Reaction of Aldehydes
with Cyclohexanone:
CH Cl saturated with NH gas-MeOH, 10:1) to give the
2
2
3
final product.
9) The following are the analytic data of catalyst 4: [a] –43.2
To a solution of 4 (12.6 mg, 0.04 mmol) in toluene (0.2 mL)
were added cyclohexanone (210 mL) and TFA (3.1 mL, 0.04
mmol). After stirring at 0 °C for 15 min, aldehyde (0.2
mmoL) was introduced. The reaction was stirred at the same
temperature until completion, and was then quenched with
2
5
(
D
1
(
c = 0.206, MeOH); mp 59–62 °C. H NMR (600 MHz,
CD OD): d = 1.57–1.72 (m, 4 H), 1.88-1.95 (m, 2 H), 2.66–
3
2
3
.71 (m, 2 H), 2.84–2.86 (dd, J = 3.90, 11.94 Hz, 1 H), 3.01–
.05 (m, 1 H), 3.71 (q, J = 8.46 Hz, 2 H), 4.21 (s, 1 H), 4.54
sat. aq solution of NH Cl. EtOAc was added to dilute the
4
1
3
(
(
br s, 1 H), 4.75 (br s, 1 H), 7.17–7.25 (m, 5 H). C NMR
150 MHz, CD OD): d = 25.6, 30.0, 39.4, 46.5, 50.5, 54.7,
mixture. The organic layer was separated, washed with
brine, dried over anhyd MgSO and concentrated under
3
4
5
7.5, 58.0, 71.8, 127.6, 128.3, 128.8, 135.4, 174.2, 175.6.
reduced pressure. The residue was purified through column
chromatography on silica gel (eluent: PE-EtOAc, 3:1) to
yield the corresponding aldol products for further analysis.
+
HRMS (ESI): m/z [M +H] calcd for C H N O : 333.1921;
found: 333.1915.
1
7
25
4
3
(
11) Further investigations, including computational studies, are
needed to fully understand why catalyst 4 is superior to 1. A
plausible explanation is that the existence of the trans-4-
hydroxyl group in 4, which had no obvious effect on the
solubility of the catalyst, favors the catalytic conformation
that led to the major diastereomer and enantiomer.
Synlett 2006, No. 15, 2419–2422 © Thieme Stuttgart · New York