Enantioselective addition of phenylacetylene to aldehydes catalyzed by polymer-supported titanium(IV) complexes of β-hydroxy amides

Article abstract of DOI:10.1002/chir.20749

A series of polymer-supported chiral β-hydroxy amides and C ₂-symmetric β-hydroxy amides have been synthesized and successfully used for the enantioselective addition of phenylacetylene to aldehydes. High yields (up to 93%) and enantioselectivities (up to 92% ee) were achieved by using polymer-supported chiral bhydroxy amide 4b. The resin 4b is reused four times, giving the product with enantioselectivity 80% ee. Fortunately, it is found that this heterogonous system is suitable not only for aromatic aldehydes but also aliphatic aldehyde.

Full text of DOI:10.1002/chir.20749

CHIRALITY 22:347–354 (2010)
Enantioselective Addition of Phenylacetylene to Aldehydes
Catalyzed by Polymer-Supported Titanium(IV) Complexes
of b-Hydroxy Amides
*
*
XIN-PING HUI, LU-NING HUANG, YA-MIN LI, REN-LIN WANG, AND PENG-FEI XU
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, People’s Republic of China
ABSTRACT
A series of polymer-supported chiral b-hydroxy amides and C2-sym-
metric b-hydroxy amides have been synthesized and successfully used for the enan-
tioselective addition of phenylacetylene to aldehydes. High yields (up to 93%) and
enantioselectivities (up to 92% ee) were achieved by using polymer-supported chiral b-
hydroxy amide 4b. The resin 4b is reused four times, giving the product with enantio-
selectivity 80% ee. Fortunately, it is found that this heterogonous system is suitable
not only for aromatic aldehydes but also aliphatic aldehyde. Chirality 22:347–354,
C
VV
2010.
2009 Wiley-Liss, Inc.
KEY WORDS: enantioselective addition; polymer-supported catalyst; titanium
tetraisopropoxide; diethylzinc; b-hydroxy amide
INTRODUCTION
polymeric Zn(salen) complex. Only 72% ee value was
obtained for this reaction.
Optically active propargyl alcohols are important build-
ing blocks for the synthesis of many organic compounds.1
Recently, the catalytic enantioselective addition of terminal
alkynes to aldehydes has generated a tremendous amount
of interest.2–11 Since the first efficient asymmetric alkynes
addition to aldehydes was demonstrated by Soai12 using
(1S,2R)-N,N-dibutylnorephedrine, many chiral ligands,
such as N-methylephedrine,13–15 BINOL and its deriva-
tives,5,10,16–21 and sulfonamides22,23 have been used suc-
cessfully in this reaction. Other chiral ligands, such as
amino alcohols,24,25 oxazoline,26–27 and imino alcohol,28
have also been reported to catalyze this reaction.
Recently, our group has developed a new b-hydroxy am-
ide chiral ligand a and C2-symmetric b-hydroxy amide b,
and successfully introduced them into the asymmetric
addition of phenacetylene to aldehydes to afford excellent
enantioselectivities.56,57 With our continuing efforts toward
the development of recyclable ligands,58 we synthesized a
series of polymer-supported chiral b-hydroxy amides and
C2-symmetric b-hydroxy amides and successfully used
them for the enantioselective addition of phenylacetylene
to aldehydes. High yields (up to 93%) and enantioselectiv-
ities (up to 92%) were achieved by using polymer-
supported chiral b-hydroxy amide 4b (Fig. 1).
Polymer-supported chiral ligands as one of the most im-
portant heterogeneous ligands have been used success-
fully in a lot of reactions.29–31 In recent years, many groups
reported the synthesis of new polymer-supported chiral
ligands and their applications in asymmetric hydrogen
transfer reaction,32–37 cyclopropanation,38,39 Aldol reac-
tion,40,41 Diels-Alder reaction,42 Michael addition,43,44 and
sulfonation reaction.45 The asymmetric alkylation of car-
bonyl groups is one of the most important methods to built
CÀÀC bond. There have been many reports about these
asymmetric reactions catalyzed by polymer-supported chi-
ral ligands such as asymmetric silylcyanation,46 allyla-
tion,47,48 and addition of dialkylzinc to aldehydes and
ketones.49–54 However, there have been far fewer exam-
ples about the enantioselective alkynylation of aldehydes
catalyzed by polymer-supported chiral ligands. Until
recently, Degni et al.50 reported the use of polymer-sup-
ported L-prolinol diverved catalysts for this addition. How-
ever, the good enantioselectiviy (91% ee) but poor yield
(45%) was obtained by using equivalent amount of chiral
ligands. Abdi and coworkers55 reported the enantioselec-
tive addition of phenylacetylene to aldehydes catalyzed by
C
EXPERIMENTAL SECTION
Melting points were determined using X-4 melting point
apparatus and were uncorrected. Optical rotations were
measured with Perkin-Elmer 341 polarimeter. 1H NMR
and 13C NMR spectra were recorded on Varian Mercury-
400 MHz spectrometer with TMS as an internal standard.
The solid state 13C NMR experiment was performed on
Bruker AV400 WB solid-state NMR instrument at 100
MHz. IR spectra were obtained on Nicollet NEXUS 670
FT-IR spectrometer. HRMS data were measured with ESI
techniques (Bruker Apex II). Elemental analyses were
Contract grant sponsor: National Natural Science Foundation of China;
Contract grant numbers: 20702022, 20621091, 2057203
*Correspondence to: Dr. Xin-Ping Hui and Peng-Fei Xu, State Key Labora-
tory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000,
People’s Republic of China. E-mail: huixp@lzu.edu.cn
Received for publication 6 January 2009; Accepted 28 March 2009
DOI: 10.1002/chir.20749
Published online 18 June 2009 in Wiley InterScience
(www.interscience.wiley.com).
VV
2009 Wiley-Liss, Inc.

348
HUI ET AL.
and stirred overnight. The reaction mixture was washed
with 1 M HCl (2 3 10 ml), saturated aqueous NaHCO3
(3 3 10 ml), and brine (3 3 10 ml). The organic layer was
dried over anhydrous MgSO4, concentrated under
reduced pressure, and the residue was recrystallized from
ethyl acetate/hexane to afford the desired monomer 3
(yield 82%); m.p. 180–1818C. [a]2D05 –115o (c 1.0, CH2Cl2).
1H NMR (400 MHz, CDCl3): d 0.90–0.99 (m, 6H), 1.54–
1.77 (m, 4H), 2.80 (dd, J 5 10.8, 14.4 Hz, 1H), 3.08 (dd, J
5 3.4, 14.2 Hz, 1H), 4.25–4.31 (m, 1H), 4.97 (s, 2H), 5.25
(d, J 5 10.8 Hz, 1H), 5.75 (d, J 5 17.6 Hz, 1H), 6.23 (d, J 5
8.8 Hz, 1H), 6.71 (dd, J 5 11.2, 17.6 Hz, 1H), 6.85 (d, J 5
8.4 Hz, 2H), 7.13 (d, J 5 8.8 Hz, 2H), 7.28–7.46 (m, 7H),
7.53 (d, J 5 8.4, 2H). 13C NMR (100 MHz, CDCl3): d 7.92,
8.28, 28.11, 28.43, 29.93, 34.54, 57.01, 69.94, 114.21, 115.13,
126.58, 127.06, 127.86, 128.66, 130.34, 131.39, 131.49,
134.98, 136.69, 136.85, 137.45, 157.53, 168.32. IR (KBr):
3487, 3355, 2958, 2878, 1633, 1536, 1513, 1240, 1017, 827,
692 cm–1. HRMS (ESI): exact mass calcd for C29H33NO3
(M1H)1: 444.2533, found: 444.2536.
Fig. 1. b-Hydroxy amide ligands.
performed on Elementar vario EL. Enantiomeric excess
values were determined by HPLC with Chiralcel OD-H col-
umn. All catalytic reactions were carried out under nitro-
gen atmosphere. L-Tyrosine and L-phenylalanine was
purchased form Alfa Aesar. Merrifild resin and 1-(chloro-
methyl)-4-vinylbenzene was purchased from Acros. Dieth-
ylzinc (1 M solution in CH2Cl2),59 5-hydroxybenzene-1,3-
dioyl dichloride,60,61 and 4-((S)-2-amino-3-ethyl-3-hydroxy-
pentyl) phenol (1)62 were synthesized according to the
literature methods, respectively. Dichloromethane was
freshly distilled from phosphorous pentoxide. Toluene,
hexane, and THF were freshly distilled from a deep-blue
solution of sodium-benzophenone under nitrogen. Ti(O-i-
Pr)4 was distilled under nitrogen prior to use.
Synthesis of Merrifield Resin-Supported Chiral Ligand 6
Compound 5 was prepared in similar procedures as
described for amino alcohol 2 and was wash sequentially
with CH2Cl2, MeOH, MeOH/H2O, acetone, MeOH, and
CH2Cl2, and dried under vacuum at 508C to afford 5 as yel-
lowish powder. Chiral ligand 6 was prepared in similar
procedures as described for 3 and was wash sequentially
with CH2Cl2, MeOH, MeOH/H2O, acetone, MeOH, and
CH2Cl2, and dried under vacuum at 508C to afford 6 as yel-
Synthesis of ( S)-1-(4-(4-Vinylbenzyloxy) phenyl)-2-
amino-3-ethylpentan-3-ol (2)
Under nitrogen, amino alcohol 1 (5.57 mmol) and dry
DMF (18 ml) were placed in a 100-ml round-bottomed lowish powder. IR (KBr): 3427, 3025, 2927, 1638, 1511,
flask. Sodium hydride (0.14 g) was added slowly with stir- 1242, 1177, 1018, 820, 701 cm–1. Anal. found: C, 81.4; H,
6.68; N, 1.76.
Synthesis of C2-Symmetric Monomer 7
ring. After the completely emission of hydrogen gas, 1-
(chloromethyl)-4-vinylbenzene (0.824 ml) was added drop-
wise and the resulting mixture was stirred at room temper-
ature for 12 h under nitrogen. Water was added and the
mixture was extracted with ethyl acetate (3 3 30 ml). The
organic layer was combined and washed sequentially with
water (30 ml), brine (3 3 30 ml), and dried over anhy-
drous MgSO4. After column chromatography (PE/EA 5
1/3), compound 2 was obtained as white solid (yield 40%);
Monomer 7 was prepared in similar procedures as
described for 3 and was purified by column chromato-
graph (PE/EA 5 1/1) as white solid (yield 81%); m.p.
1
103–1048C. [a]2D05 –1138 (c 5 1.0, CH2Cl2). H NMR (400
MHz, CDCl3): d 0.86–0.97 (m, 12H), 1.51–1.75 (m, 8H),
2.46 (br, 2H), 2.78 (dd, J 5 10.8, 14.2 Hz, 2H), 3.07 (dd, J
5 3.8, 14.2 Hz, 2H), 4.28–4.34 (m, 2H), 4.93 (s, 4H), 5.24
(d, J 5 12.0 Hz, 2H), 5.73 (d, J 5 18.4 Hz, 2H), 6.30 (d, J 5
8.8 Hz, 2H), 6.69 (dd, J 5 10.8, 17.6 Hz, 2H), 6.85 (d, J 5
8.8 Hz, 4H), 7.12 (d, J 5 8.8 Hz, 4H), 7.27–7.38 (m, 9H),
7.56 (d, J 5 8.0 Hz, 2H), 7.75 (s, 1H). 13C NMR (100 MHz,
CDCl3): d 7.61, 7.89, 27.48, 27.91, 34.15, 56.41, 69.47,
76.88, 113.86, 114.58, 125.04, 126.17, 127.56, 128.84,
129.40, 130.04, 131.10, 134.78, 136.29, 137.03, 157.10,
167.80. IR (KBr): 3410, 2967, 2938, 1643, 1512, 1242, 1176,
1015, 987, 827 cm–1. HRMS (ESI): exact mass calcd for
C52H60N2O6 (M1H)1: 809.4524, found: 809.4533.
m.p. 72–738C. [a]205 –268 (c 5 1.0, CH2Cl2). 1H NMR
D
(400 MHz, CDCl3): d 0.92–0.97 (m, 6H), 1.41–1.67 (m,
4H), 2.25 (dd, J 5 11.6, 14.0 Hz, 1H), 2.91 (d, J 5 12.0 Hz,
1H), 5.04 (s, 2H), 5.26 (d, J 5 10.8 Hz, 1H), 5.76 (d, J 5
17.6 Hz, 1H), 6.72 (dd, J 5 10.8, 17.6 Hz, 1H), 6.92 (d, J 5
8.4 Hz, 2H), 7.10 (d, J 5 8.4 Hz, 2H), 7.38–7.44 (m, 4H).
13C NMR (100 MHz, CDCl3): d 7.56, 26.40, 27.74, 36.95,
57.18, 69.57, 74.18, 113.88, 114.87, 126.22, 127.47, 129.89,
132.13, 136.26, 136.46, 137.09, 157.18. IR (KBr): 3341,
3186, 2965, 2936, 2878, 1608, 1152, 1387, 1293, 1245, 1004,
907, 797 cm–1.
Synthesis of N-(( S)-1-(4-(4-Vinylbenzyloxy) phenyl)-3-
ethyl-3-hydroxypentan-2-yl)benzamide (3)
Synthesis of C2-Symmetric Compound 10
Compound 10 was prepared in similar procedures as
A solution of benzoyl chloride (3.3 mmol) in CH2Cl2 (10 described for 3 and was purified by column chromato-
ml) was added to a solution of amino alcohol 2 (3 mmol) graph (PE/EA 5 2/1) as white solid (yield 66%); m.p. 82–
1
and Et3N (3.3 mmol) in CH2Cl2 (10 ml) at 08C. The reac- 838C. [a]2D05 1358 (c 5 1.0, CH2Cl2). H NMR (400 MHz,
tion mixture was allowed to warm to room temperature CDCl3): d 3.13–3.26 (m, 4H), 3.73 (s, 6H), 4.97–5.00 (m,
Chirality DOI 10.1002/chir

POLYMER-SUPPORTED CHIRAL ꢀ-HYDROXY AMIDE
349
2H), 7.15–7.36 (m, 15H), 7.43 (s, 1H). 13C NMR (100 crashed and collected (<100 mesh) to afford the product
MHz, CDCl3): d 37.49, 52.36, 54.18, 116.55, 117.81, 126.94, as white solid powder.
128.45, 129.01, 134.80, 135.89, 157.20, 166.73, 172.40. IR
4a: 13C Solid State NMR (100 MHz): d 9, 27, 40, 77, 128,
(KBr): 3335, 3030, 2953, 1741, 1647, 1529, 1438, 1219, 750, 145, 180, 194, 228. IR (KBr): 3425, 3025, 2923, 1640, 1512,
700 cm–1.
1449, 1241, 1176, 1020, 819, 759, 698, 539 cm–1. Anal.
found: C, 82.80; H, 6.90; N, 1.67.
Synthesis of C2-Symmetric Compound 11
4b: IR (KBr): 3428, 3025, 2921, 1637, 1512, 1449, 1240,
1177, 1024, 820, 757, 698, 538 cm–1. Anal. found: C, 85.72;
H, 7.78; N, 1.12.
8a: IR (KBr): 3426, 3025, 2924, 1653, 1511, 1451, 1241,
1017, 819, 760, 700 cm–1. Anal. found: C, 81.74; H, 6.84; N,
1.74.
8b: IR (KBr): 3429, 3025, 2921, 1661, 1603, 1511, 1493,
1450, 1241, 1026, 756, 698 cm–1. Anal. found: C, 87.35; H,
6.71; N, 0.76.
13: IR (KBr): 3416, 3351, 3025, 2924, 1647, 1594, 1514,
1450, 1347, 1135, 1032, 751, 698, 540 cm–1. Anal. found: C,
81.27; H, 6.87; N, 2.17.
Compound 11 was prepared in similar procedures as
described for amino alcohol 2 and was purified by column
chromatograph (PE/EA 5 1.5/1) as white solid (yield
1
46%); m.p. 102–1038C. [a]2D05 1518 (c 5 1.0, CH2Cl2). H
NMR (400 MHz, CDCl3): d 3.17–3.31 (m, 4H), 4.76 (s,
6H), 5.03–5.08 (m, 4H), 5.27 (d, J 5 11.2 Hz, 1H), 5.77 (d,
J 5 17.6 Hz, 1H), 6.72 (dd, J 5 10.8, 17.6 Hz, 1H), 6.70–
6.76 (br, 2H), 7.13–7.46 (m, 16H), 7.59 (s, 1H). 13C NMR
(100 MHz, CDCl3): d 37.59, 52.29, 53.89, 69.86, 114.09,
116.70, 117.30, 126.29, 127.00, 127.73, 128.47, 129.04,
135.37, 135.91, 136.20, 137.37, 158.71, 166.05, 172.17. IR
(KBr): 3247, 3030, 2951, 1744, 1645, 1532, 1438, 1360,
1215, 1034, 828, 747, 700 cm–1.
General Procedure for Asymmetric Addition of
Phenylacetylene to Aldehydes
Synthesis of C2-Symmetric Monomer 12
Under dry nitrogen, the polymer-supported ligand (0.04
mmol) and Ti(O-i-Pr)4 (0.14 mmol) were mixed in solvent
(1.0 ml) at room temperature and stirred for 1 h. Then a so-
lution of diethylzinc (0.6 mmol, 1.0 M in CH2Cl2) was
added. After the mixture was stirred at room temperature
for 2 h, phenylacetylene (0.6 mmol) was added and stirred
for another 1 h. The solution was treated with aldehyde (0.2
mmol). After the reaction was completed (TLC), the reac-
tion solution was cooled to 08C and quenched by 0.5 M
aqueous HCl. The mixture was extracted with diethyl ether
(3 3 10 ml), washed with brine (3 3 15 ml), dried with an-
hydrous Na2SO4, and concentrated under vacuum. The
crude product was purified by column chromatography
(silica gel, PE : EA 5 8:1) to give the propargyl alcohol.
A solution of 11 (1.84 mmol) in THF (10 ml) was added
to a solution of EtMgBr (18.4 mmol) in THF at 08C. The
reaction mixture was allowed to warm to room tempera-
ture and stirred overnight. The saturated aqueous solution
of ammonium chloride was added dropwisely to the mix-
ture under 08C. The reaction mixture was then extracted
with ethyl acetate (3 3 30 ml), and the organic layer was
washed with saturated aqueous NaHCO3 (3 3 10 ml), and
brine (3 3 10 ml). The organic layer was dried over anhy-
drous MgSO4, concentrated under reduced pressure, and
the residue was purified by column chromatograph to
afford the desired monomer 12 (yield 89%); m.p. 137–
1388C. [a]2D05 –988 (c 5 1.0, CH2Cl2). 1H NMR (400 MHz,
CDCl3): d 0.79–0.88 (m, 12H), 1.49–1.77 (m, 8H), 2.51 (br,
2H), 2.75–2.86 (m, 2H), 3.09–3.19 (m, 2H), 4.32–4.39 (m,
2H), 4.82–5.00 (m, 2H), 5.28 (d, J 5 11.2 Hz, 1H), 5.78 (d,
J 5 17.6 Hz, 1H), 6.28 (br, 2H), 6.73 (dd, J 5 10.8, 17.6 Hz,
1H), 7.12–7.43 (m, 17H). 13H NMR (100 MHz, CDCl3): d
8.03, 8.17, 27.81, 28.38, 29.92, 35.46, 56.76, 70.17, 77.25,
114.59, 116.27, 117.42, 126.50, 126.69, 127.43, 128.22,
128.58, 128.92, 129.40, 135.72, 136.59, 137.86, 139.12,
167.25. IR (KBr): 3416, 3281, 2967, 2938, 1744, 1644, 1533,
1356, 1137, 1035, 827, 745, 698 cm–1. HRMS (ESI): exact
mass calcd for C43H52N2O5 (M1Na)1: 699.3768, found:
699.3765.
General Procedure for Restoration of Polymer-
Supported Ligand 4b
After one catalytic cycle, the polymer-supported ligand
4b was washed sequentially with 1 M HCl (30 ml), MeOH
(30 ml), mixture of MeOH and CH2Cl2 (1:1, 30 ml) and
CH2Cl2 (30 ml), then dried under vacuum at 508C for 18 h
before reuse.
RESULTS AND DISCUSSION
Synthesis of Polymer-Supported b-Hydroxy Amides
Generally, there are two methods to synthesis polymer-
supported chiral ligands: (a) directly grafted the chiral
ligands onto the surface of Merrifield resin; (b) derivation
General Procedure for Synthesis of Polymer-Supported
Chiral Ligands 4a-b, 8a-b, and 13
The synthesis of polymer-supported chiral ligands 4a as of the chiral ligands with terminal olefinic link, and copoly-
the sample: Under nitrogen atmosphere, compound 3 (2 merization of the ligands with other monomers to form the
mmol), styrene (7.8 mmol), divinyl benzene (0.2 mmol) polymer-supported chiral ligands. In this article, both
and AIBN (0.125 mmol) were solved in THF (4 ml). H2O methods were introduced to synthesize polymer-supported
(20 ml) was added to the mixture and stirred at room tem- b-hydroxy amides. As shown in scheme 1, amino alcohol
perature for 1 h. Then the mixture was reflux for 48 h 1 was synthesized from L-tyrosine. Compound 1 coupled
under N2 to afford white solid. The solid was washed with 1-(chloromethyl)-4-vinylbenzene to form compound
sequentially with H2O, THF, acetone, MeOH, and CH2Cl2. 2. The reaction of 2 with benzoyl chloride yielded mono-
After dried under vacuum at 608C for 48 h, the solid was mer 3. Polymer-supported amino alcohols 4a-b were
Chirality DOI 10.1002/chir

350
HUI ET AL.
Scheme 1. Synthesis of polymer-supported chiral ligands 4a-b and 6.
synthesized through copolymerization of monomer 3 with through the reaction of 2 and isophthaloyl dichloride. By
styrene and divinyl benzene. Compound 1 was directly using the same method with 4, polymer-supported ligands
grafted onto Merrifield resin to form polymer-supported 8a-b were obtained with different cross linking and the
amino alcohol 5. Reaction of polymer-supported 5 amount of monomers.
with benzoyl chloride yielded the polymer-supported
There is another strategy to synthesize polymer-sup-
b-hydroxy amide 6. The amount of chiral ligand grafted ported C2-symmetric b-hydroxy amide as shown in
onto polymers was calculated from elemental analysis of scheme 3. L-Phenylalanine derived compound 9 reacted
nitrogen.
with 5-hydroxybenzene-1,3-dioyl dichloride to yield C2-
C2-Symmetric b-hydroxy amide
b
performed good symmetric 10. Compound 10 coupled with 1-(chloro-
catalytic reactivity in the enantioselective addition of methyl)-4-vinylbenzene to form compound 11. Monomer
phenylacetylene to aldehydes. Herein, we successfully 12 was obtained by the reaction of 11 with EtMgBr at
designed and synthesized polymer-supported C2-symmet- ambient temperature. C2-Symmetric b-hydroxy amide 13
ric b-hydroxy amides in order to further improve the ee was synthesized by the same copolymerization of polymer-
value. As shown in scheme 2, monomer 7 was obtained supported ligand 4a.
Scheme 2. Synthesis of polymer-supported chiral ligands 8a-b.
Chirality DOI 10.1002/chir

POLYMER-SUPPORTED CHIRAL ꢀ-HYDROXY AMIDE
351
Scheme 3. Synthesis of polymer-supported chiral ligand 13.
Enantioselective Addition of Phenylacetylene to
Aldehyde Catalyzed by Polymer-Supported Titanium(IV)
Complexes of b-Hydroxy Amides
30% caused the increasing of ee value (88% ee) (Table 1,
Entries 3 and 10). For the catalytic system of the resin 4b
containing 10% ligand loading, the product was obtained in
high yield (85%) with a slight increase in enantioselectivity
(87% ee) (Table 1, Entry 11). The titanium complex of 20
mol % resin 6 was examined to afford propargyl alcohol in
only 58% yield and 49% ee (Table 1, Entry 12). The low
yield and ee is attributed to interferences of close proxim-
ities of active catalytic metal centers in the resin 6 having
98% ligand loading. This study reveal that the immobilized
catalytic system of 4b with 10% ligand loading is superior
to the catalytic systems of resins 4a and 6 having higher
ligand loadings of 20% and 98%, respectively.
First, monomer 3 was chosen as model ligand to cata-
lyze the enantioselective addition of phenylacetylene to
benzaldehyde, 1,3-diphenylprop-2-yn-1-ol was obtained in
85% yield, and 89% ee (Table 1, Entry 1). To elucidate
effects of ligand loadings, catalytic system of 4a having
the 20% ligand loading was then examined. The results
showed that the yield and ee value of propargyl alcohol
were raised sharply with increasing the amount of Ti(O-i-
Pr)4. Further increasing the amount of Ti(O-i-Pr)4 resulted
in a slightly decrease in ee value, whereas, the reaction
yield decreased deeply (Table 1, Entries 2–6). The best ee
value 86% was obtained with Ti(O-i-Pr)4/ligand of 3.5/1
(Table 1, Entry 3). Four solvents were examined and tolu-
ene was found to be the best choice (Table 1, Entries 3, 7-
9). Improving the amount of the chiral ligand from 20% to
The C2-symmetric monomers and corresponding poly-
mer-supported ligands were also used in the enantioselec-
tive addition of phenylacetylene to benzaldehyde. Mono-
mer 7 has good catalytic reactivity (Table 2, Entry 1),
whereas the polymer-supported 8a and 8b have poor or
TABLE 1. Asymmetric addition of phenylacetylene to benzaldehyde catalyzed by ligands 3, 4a-b, and 6a
Entry
Ligand (mol %)
Ti(OiPr)4/Ligand
Solvent
Yield (%)b
ee (%)c (Config.)
1
2
3
4
5
6
7
8
3 (20)
4a (20)
4a (20)
4a (20)
4a (20)
4a (20)
4a (20)
4a (20)
4a (20)
4a (30)
4b (20)
6 (20)
3/1
3/1
3.5/1
4/1
5/1
6/1
3.5/1
3.5/1
3.5/1
3.5/1
3.5/1
3.5/1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
CH2Cl2
Hexane
Toluene
Toluene
Toluene
85
50
73
83
76
56
49
56
54
80
85
58
89 (R)
77
86
85
83
83
43
86
86
9
10
11
12
88
87
49
aZnEt2/Phenylacetylene/PhCHO 5 0.6/0.6/0.2 mmol. Reaction temperature: rt. Reaction time: 18 h.
bIsolated yields.
cDetermined by HPLC with Chiralcel OD-H column.
Chirality DOI 10.1002/chir

352
HUI ET AL.
TABLE 2. Asymmetric addition of phenylacetylene to
benzaldehyde catalyzed by ligands 7, 8a-b, and 13a
used for the next cycle. The resin 4b was reused four
times to afford 1,3-diphenylprop-2-yn-1-ol in high yields.
However, enantioselectivities decrease slightly from 87,
85, 82, to 80% ee.
Ligand
(mol %)
Ti(OiPr)4/
Ligand
Yield
(%)b
ee (%)c
(Config.)
Entry
1
2
3
4
7 (10)
8a (10)
8b (10)
13 (10)
3/1
3.5/1
3.5/1
3.5/1
93
66
83
80
92 (R)
50
78
CONCLUSION
In conclusion, a series of polymer-supported chiral b-
hydroxy amides and C2-symmetric b-hydroxy amides
have been synthesized and successfully used for the
enantioselective addition of phenylacetylene to aldehydes.
High yields (up to 93%) and enantioselectivities (up to
92%) were achieved by using polymer-supported chiral b-
hydroxy amide 4b. The resin 4b is reused four times,
giving the product with enantioselectivity 80% ee. Fortu-
nately, it is found that this heterogeneous system is suita-
ble not only for aromatic aldehydes but also aliphatic
aldehyde.
74
aReaction temperature: rt. Reaction time: 18 h.
bIsolated yields.
cDetermined by HPLC with Chiralcel OD-H column.
moderate catalytic activities (Table 2, Entries 2 and 3). It
may be caused by the higher mechanical robustness of
8a–b than 4, and less swelling capacity. Another C2-sym-
metric chiral ligand 13 also have moderate enantioselec-
tivities (Table 2, Entry 4).
Compared with the catalytic activities of different poly-
mer-supported ligands, ligand 4b was chose as the best
suitable ligands. Generalities of the heterogeneous cata-
lytic system of resin 4b were then examined on a variety
of aldehydes. As the results summarized in Table 3, the
desired propargyl alcohols in excellent isolated yields
from 84 to 93% with good enantioselectivities from 86 to
92% were achieved. The best enantioselectivity of 92% ee
was obtained for the alkynylation of 4-chlorobenzaldehyde
(Table 3, Entry 4). Furthermore, it was worthy to be
noticed that this heterogeneous catalytic system was also
suitable for the aliphatic aldehyde and good enantioselec-
tivity from 80 to 83% were obtained (Table 3, Entries 7–9).
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