l-Proline-derived tertiary amino alcohol as a new chiral ligand for enantioselective alkynylation of aldehydes

Article abstract of DOI:10.1016/j.tetlet.2008.12.030

The easily prepared chiral tertiary amino alcohol 1a was found to catalyze the reaction of alkynylzinc reagents with various aldehydes to generate chiral propargylic alcohols with moderate-to-good enantioselectivities. The mechanism of the reaction is als

Full text of DOI:10.1016/j.tetlet.2008.12.030

Tetrahedron Letters 50 (2009) 926–929
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
L-Proline-derived tertiary amino alcohol as a new chiral ligand
for enantioselective alkynylation of aldehydes
Zhou Xu a, Nan Wu b, Zhenhua Ding a, Ting Wang a, Jincheng Mao a, Yawen Zhang a,
*
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China
b Department of Aviation Oil and Material, Xuzhou Airforce College, Xuzhou 222110, Jiangsu, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The easily prepared chiral tertiary amino alcohol 1a was found to catalyze the reaction of alkynylzinc
reagents with various aldehydes to generate chiral propargylic alcohols with moderate-to-good enanti-
oselectivities. The mechanism of the reaction is also discussed in this Letter. A novel theoretical compu-
tation of those evaluated ligands was introduced which may supply valuable experience to help
designing new chiral ligands.
Received 10 October 2008
Revised 2 December 2008
Accepted 5 December 2008
Available online 13 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The catalytic enantioselective addition of terminal alkynes to
aldehydes has generated great amount of interest in recent years.
The resulting propargylic alcohols are versatile building blocks
for many chiral compounds.1–4 Although some impressive results
have been obtained with several effective asymmetric catalysts,5
most of these ligands are derived from chiral binol or (ꢀ)-N-methyl
ephedrine. Thus, it is still desirable to develop new types of chiral
catalysts which are greatly needed to probe how the chiral cata-
lysts act on the reaction and how to develop new types of chiral li-
Screening of ligands in the reaction between benzaldehyde and
phenylacetylene in toluene, we found that ligand 1a16 gave the
best result with 77% ee (Fig. 1). Interestingly, although these
ligands were derived from the same starting material, different
configurations of the products were observed (Fig. 1). This will
be discussed in this Letter later.
Encouraged by the results shown inFigure 1, we chose ligand 1a
to further our study. Then the effects of the reaction conditions,
such as the choice of solvents, the reaction temperature, and the
amount of ligand 1a were investigated.
At room temperature, the best ee was obtained in toluene
(Table 1, entry 3). Lower reaction temperatures did not improve
the enantioselectivities (Table 1, entries 10 and 11). Increasing
the amount of ligand 1a to 30 mol % improved the selectivity
(80% ee) slightly (Table 1, entry 8), while further increasing the
amount of the ligand does not increase the ee anymore (Table 1,
entry 9). Decreasing the amount of 1a to 10 mol % gave the chiral
product with 69% ee (Table 1, entry 7). Additives (1.0 mol %) were
also investigated. Unfortunately, they did not show any beneficial
effects on this reaction.
gands.
in many asymmetric reactions, especially as chiral ligands or chiral
resources.6 Herein, we report an
-proline-derived tertiary amino
L-Proline and its derivatives have shown powerful utilities
L
alcohol 1a, as a new chiral ligand for the catalytic asymmetric alk-
ynylation of aldehydes, as our continuing interest.7 Several papers
have reported the utilization of tertiary amino alcohols as ligands
to catalyze the asymmetric alkynylation of aldehydes,8–12 but
few of them have discussed the mechanism of this reaction. In this
Letter, the mechanism of the reaction will be discussed, and theo-
retical explanation based on calculations will be introduced to help
us understand how to design new types of chiral ligands more
successfully.
Initially, we synthesized 1b as a ligand for the alkynylation of
benzaldehyde which resulted in the formation of an adduct of
65% ee in toluene. This was a promising result. In order to screen
more effective ligands and study the relationships between ligand
structure and the enantioselectivity, we prepared ligands 1a–h
(Scheme 1). Ligands 1a, 1b, 1c, 1d, 1e, and 1g were prepared
according to the procedure described by Kanth;13 ligand 1f was ob-
tained from the diphenyl prolinol by N-tosylation;14 and ligand 1h
was prepared following the literature procedure.15
Ph
Ph
Et
Ph
Ph
Ph
Ph
N
N
N
Et
N
HO
HO
HO
HO
1c
1d
1b
1a
1e
Ph
Ph
Ph
Ph
OH
Ph
Ph
N
Ph
Ph
N
HO
N
N
HO
C
EtO2
HO
Ts
O
Ph
1h
1f
1g
* Corresponding author. Tel.: +86 0512 65880340; fax: +86 0512 65880305.
E-mail address: zhangyw@suda.edu.cn (Y. Zhang).
Scheme 1. Evaluated ligands in this Letter.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.030

Z. Xu et al. / Tetrahedron Letters 50 (2009) 926–929
927
Table 2
Yield ee
Enantioselective alkynylation of various aldehydes with 1aa
90
80
1b
1c 1d
1e
1a
OH
O
H
1a / Toluene
+
H
R'
R
70
R'
Et2Zn, r.t
60
R
50
Entry
Aldehyde
R
Yieldb (%)
eec (%)
40
1
2
3
4
5
6
7
8
9
10
11
12
13
Benzaldehyde
2-Anisaldehyde
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-CH3Ph
Me3Si
76
70
61
87
71
83
78
82
87
80
85
63
60
80
77
83
74
83
82
72
75
75
79
73
78
71
30
20
2-Bromobenzaldehyde
3-Bromobenzaldehyde
2-Chlorobenzaldehyde
3-Chlorobenzaldehyde
4-Chlorobenzaldehyde
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
a
-Naphthaldehyde
b-Naphthaldehyde
2-Thiophenaldehyde
2-Fluorobenzaldehyde
2-Chlorobenzaldehyde
Benzaldehyde
1g 1h
1f
a
All the reactions were processed under argon at room temperature for 24 h,
phenylacetylene/Et2Zn/benzaldehyde/ligand = 2:2:1:0.3.17
Figure 1. Yields and ees of the product catalyzed by the evaluated ligands in this
b
Isolated yield.
Letter.
c
The enantiomeric excess was determined by chiral HPLC analysis of the cor-
responding products on a Chiralcel OD-H column. The configuration of the product
is R assigned by comparing the retention time to the literature.18
Having optimized the alkynylation of benzaldehyde with phen-
ylacetylene in the presence of chiral ligand 1a, we decided to
screen a series of aldehydes and acetylenes to evaluate the scope
of this reaction. As shown by the results summarized in Table 2,
good enantioselectivities were achieved for most of the substrates.
Aromatic aldehydes bearing electron-withdrawing group at the
ortho-position gave better results than that at the meta- or para-
positions (Table 2, entries 2–9). For other acetylenes, good results
could also be obtained for the reaction. For example, 78% ee was
obtained for the addition of 4-methylphenylacetylene to 2-chloro-
benzaldehyde (Table 2, entry 12). The reaction of phenylacetylene
addition to the aliphatic aldehydes was also observed, but only 46%
ee was obtained.
lated to the substituent at N atom in the ligand. Ligands with elec-
tron-donating group at the N atom give the (R)-form product, while
ligands with electron-withdrawing group give the inverted config-
uration (Fig. 1). These attracted us to find out the relationships be-
tween the ligand structure and the enantioselectivity/the
configuration of the product. If we know these well, it may help
us to design new chiral ligands.
In order to explain the correlation between the electronic sim-
ilarity of the coordinated atoms (N and O) and the ee of the product
more convincingly, we calculated the NBO charge of the coordi-
nated atoms using the GAUSSIAN 03 programs.19 The results are listed
in Table 3.
As we know the suitable match between the ligand and the cen-
ter metal is very important for the asymmetric catalytic reactions.
Interestingly, the configuration of the product seems to be corre-
Comparing ligands 1a–e, the NBO charge of the N atom and O
atom in each ligand was correlated to the enantioselectivity of
Table 1
Optimization of the reaction conditionsa
OH
1a / Toluene
+
H
CHO
Et2Zn, r.t
Entry
Solvent
T
Additive
Yieldb
eec (%)
1
2
3
4
5
THF
Et2O
Toluene
Hexane
DCM
rt
rt
rt
rt
rt
rt
rt
rt
—
—
—
—
—
—
—
—
54
67
65
59
64
72
65
70
69
61
59
71
69
71
59
61
77
71
53
73
69
80
79
65
78
77
77
77
6
DME
7d
8e
9f
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
rt
—
—
—
10
11
12
13
14
0 °C
ꢀ25 °C
rt
rt
rt
Et3N
DMAP
DiMPEG
a
All the reactions were processed under argon at room temperature for 24 h, phenylacetylene/Et2Zn/benzaldehyde/ligand = 1:1:0.5:0.1.
b
c
d
e
f
Isolated yield.
The enantiomeric excess was determined by chiral HPLC analysis of the corresponding products on a Chiralcel OD-H column.
10 mol % ligand was used.
30 mol % ligand was used.
40 mol % ligand was used.

928
Z. Xu et al. / Tetrahedron Letters 50 (2009) 926–929
Table 3
and the theoretical calculations about those evaluated ligands with
GAUSSIAN 03 program have also been performed, the results of
The calculated NBO charge of N and O atoms in ligands 1a–fa
a
which may supply us useful guidance in designing new chiral
ligands.
Ligand
NBO charge
N
O
Db
1a
1b
1c
1d
1e
1f
ꢀ0.517
ꢀ0.516
ꢀ0.521
ꢀ0.517
ꢀ0.516
ꢀ0.778
ꢀ0.762
ꢀ0.765
ꢀ0.782
ꢀ0.764
ꢀ0.765
ꢀ0.758
0.245
0.249
0.261
0.247
0.249
Acknowledgments
We thank Dr. Ni, Nanjing University, for the calculation of the
NBO charges of the ligands in this letter. We are grateful to the
Key Laboratory of Organic Synthesis of Jiangsu Province for finan-
cial support.
ꢀ0.020
a
The results were calculated by using a GAUSSIAN 03 program.
b
D
= N–O.
References and notes
1. Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH: Weinheim,
1995.
2. Fox, M. E.; Li, C.; Marino, J. P. J.; Overman, L. E. J. Am. Chem. Soc. 1999, 121,
5467–5480.
3. Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116, 3151–3152.
4. Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1994, 116, 6457–6458.
5. Selective examples: (a) Frantz, D. E.; Fässler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806–1807; (b) Xu, M. H.; Pu, L. Org. Lett. 2002, 4, 4555–4557; (c) Li,
X.; Lu, G.; Kwok, W. H.; Chan, A. S. C. J. Am. Chem. Soc. 2002, 124, 12636–12637;
(d) Liu, Q. Z.; Xie, N. S.; Luo, Z. B.; Cui, X.; Cun, L. F.; Gong, L. Z.; Mi, A. Q.; Jiang, Y.
Z. J. Org. Chem. 2003, 68, 7921–7924; (e) Xu, Z.; Wang, R.; Xu, J.; Da, C.; Yan, W.;
Chen, C. Angew. Chem., Int. Ed. 2003, 42, 5747–5749; (f) Dahmen, S. Org. Lett.
2004, 6, 2113–2116; (g) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 13760–13761; (h) Trost, B. M.; Weiss, H.; Von Wangelin,
A. J. J. Am. Chem. Soc. 2006, 128, 8–9; (i) Asano, Y.; Hara, K.; Ito, H.; Sawamura,
M. Org. Lett. 2007, 9, 3901–3904; (j) Liebehentschel, S.; Cvengroš, J.; Von
Wangelin, A. J. Synlett 2007, 16, 2574–2578; (k) Yang, F.; Xi, P. H.; Yang, L.; Lan,
J. B.; Xie, R. G.; You, J. S. J. Org. Chem. 2007, 72, 5457–5460.
N
O
O
N
Et
O
Et
Zn
Zn
Et
Zn
Ph
Et
Zn
H
O
H
Ph
TS-1
TS-2
Figure 2. The proposed transition states of the reaction.
6. (a) List, B. Tetrahedron 2002, 58, 5573–5590; (b) Corey, E. J.; Hetal, C. J. Angew.
Chem., Int. Ed. 1998, 37, 1986–2012.
7. (a) Xu, Z.; Mao, J. C.; Zhang, Y. W. Org. Biomol. Chem. 2008, 6, 1288–1292; (b)
Mao, J.; Wan, B.; Wu, F.; Lu, S. Chirality 2005, 17, 245–249; (c) Mao, J.; Wan, B.;
Wu, F.; Lu, S. J. Org. Chem. 2004, 69, 9123–9127.
8. Pizzuti, M. G.; Superchi, S. Tetrahedron: Asymmetry 2005, 16, 2263–2269.
9. Lu, G.; Li, X. S.; Zhou, Z. Y.; Chan, W. L.; Albert, A. S. C. Tetrahedron: Asymmetry
2001, 12, 2147–2152.
10. Koyuncu, H.; Dogan, Ö. Org. Lett. 2007, 9, 3477–3479.
11. Rajesh, M. K.; Vinod, K. S. Tetrahedron Lett. 2003, 44, 5347–5349.
12. Ekström, J.; Zaitsev, A. B.; Adolfsson, H. Synlett 2006, 885–888.
13. Kanth, J. V. B.; Perisasamy, M. Tetrahedron 1993, 49, 5127–5132.
14. Yang, S. D.; Shi, Y.; Sun, Z. H.; Zhao, Y. B.; Liang, Y. M. Tetrahedron: Asymmetry
2006, 17, 1895–1900.
15. Müller, S.; Afraz, M. C.; De Gelder, R.; Ariaans, G. J. A.; Kaptein, B.; Broxterman,
Q. B.; Bruggink, A. Eur. J. Org. Chem. 2005, 6, 1082–1096.
16. Character data of ligand 1a: Careful evaporation of a solution of 1a in methanol
gave a single crystal which is suitable for crystallographic analysis. Mp 108–
110 °C; ½a 2D5
ꢁ
+71.0 (c 1.01, acetone); 1H NMR (400 MHz, CDCl3) d 7.81 (d,
Figure 3. X-ray structure of ligand 1a.
J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.30–7.27 (m, 4H), 7.16–7.09 (m, 2H),
6.80 (s, 2H), 4.87 (s, 1H), 3.99 (dd, J = 9.4, 5.3 Hz, 1H), 3.43–3.32 (m, 1H), 3.13
(d, J = 12.2 Hz, 1H), 2.63 (td, J = 9.2, 4.5, 4.5 Hz, 1H), 2.48–2.34 (m, 1H), 2.21 (s,
3H), 2.17 (s, 6H), 1.93 (ddd, J = 17.8, 11.1, 6.5 Hz, 1H), 1.68 (ddd, J = 12.8, 8.4,
4.1 Hz, 1H), 1.60–1.48 (m, 2H); 13C NMR (100 MHz, CDCl3) d 148.8, 147.6,
137.8, 136.7, 133.1, 129.4, 128.5, 126.8, 126.5, 125.5, 78.1, 72.6, 54.6, 54.0,
40.7, 30.5, 24.3, 21.4, 21.2; IR (cmꢀ1): 3401, 3051, 2968, 2937, 2888, 2842,
1448; HRMS (EI) calcd for [C27H31NOꢀH2O]+ requires m/z 367.2300, found
367.2282. Selective crystal structure data: C27H31NO, triclinic, space group P1,
the product. Those with large margin gave the product with lower
ee, while ligand 1a with the smallest margin gave the product with
the best ee which indicates that the smallest
may form the most selective catalyst with Et2Zn. Interestingly, the
calculated value for ligand 1f is <0. This is in accordance with the
D (N–O) of the ligand
D
a = 6.0379(10) Å, b = 12.783(2) Å, c = 15.101(2) Å,
a = 96.757(17)°, b = 98.206
(16)°,
c
= 103.14(2)°, V = 1109.7(3) Å3, Z = 2, T = 293(2) K. For the detailed
observed inverted configuration. Unfortunately, calculation on li-
gand 1g and 1h did not give similar results, although both of them
gave configuration-inverted product. This is probably because of
the presence of another coordinative oxygen atom in C@O, which
may result in complicated coordination.
information of the crystal data, please see CCDC 695642.
17. General experimental procedure for the addition of alkyne to aldehyde: To a
solution of ligand 1a (0.0579 g, 0.15 mmol) in dry toluene (2.0 ml) at room
temperature was added a solution of ZnEt2 (15% in hexane, 1.1 ml). After
the mixture was stirred at room temperature for 2.0 h, phenylacetylene
(110
ll, 1.0 mmol) was added and the stirring continued for another 2.0 h.
The proposed transition states are shown in Figure 2. The pro-
posed TS-1 which may give the lower energy was the favorable
way to give the R configuration product, while TS-2 which was
the unfavorable transition state gave the product with the inverted
configuration (Fig. 3).
In conclusion, we have successfully developed an efficient cata-
lyst system for the enantioselective synthesis of propargylic alco-
hols via alkynylzinc addition to various aldehydes. The study has
shown that the chiral ligand 1a in the absence of Lewis acids can
form an active catalyst with Et2Zn which could afford products
with up to 83% ee. The mechanism of the reaction was proposed
The white solution was treated with benzaldehyde (50
l
l, 0.5 mmol) at 0 °C
and stirred at room temperature for 24 h. After the reaction was
completed, it was cooled to 0 °C and quenched by 5% aqueous HCl
(2.0 ml). The mixture was extracted with ethyl acetate (EtOAc) (3 ꢂ 10 ml).
The organic layer was dried over Na2SO4 and concentrated under vacuum.
The residue was purified by flash column chromatography (silica gel H,
EtOAc/petroleum ether = 1:8) to give the pure product. 76% yield. 80% ee
determined by HPLC analysis (Chiralcel OD-H column, IPA/hexane = 20:80).
Retention time: tmajor = 7.57 min, tminor = 10.51 min. 1H NMR (400 MHz,
CDCl3) d 7.62 (d, J = 7.2 Hz, 2H), 7.48–7.25 (m, 8H), 5.69 (s, 1H), 2.36 (s,
1H); 13C NMR (100 MHz, CDCl3) d 141.1, 132.2, 129.2, 129.1, 128.9, 128.8,
127.2, 122.9, 89.1, 87.2, 65.6.
18. Ramachandran, P. V.; Teodorovic, A. V.; Rangaishenvi, M. V.; Brown, H. C. J. Org.
Chem. 1992, 57, 2379–2386.

Z. Xu et al. / Tetrahedron Letters 50 (2009) 926–929
929
19. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;
Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J. ; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. GAUSSIAN 03, revision B.04; Gaussian,
Inc., Wallingford, CT, 2004.