Chiral Lewis acid-catalyzed asymmetric Baylis-Hillman reactions

Article abstract of DOI:10.1021/jo026318m

An effective chiral Lewis acid-catalyzed asymmetric Baylis-Hillman reaction is described. Good to high enantioselectivities were obtained using 3 mol % chiral catalyst. Novel camphor-derived dimerized ligands were prepared from the condensation of (+)-ket

Full text of DOI:10.1021/jo026318m

Ch ir a l Lew is Acid -Ca ta lyzed Asym m etr ic Ba ylis-Hillm a n
Rea ction s
Kung-Shuo Yang, Wei-Der Lee, J ia-Fu Pan, and Kwunmin Chen*
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan 116, ROC
kchen@scc.ntnu.edu.tw
Received August 14, 2002
An effective chiral Lewis acid-catalyzed asymmetric Baylis-Hillman reaction is described. Good
to high enantioselectivities were obtained using 3 mol % chiral catalyst. Novel camphor-derived
dimerized ligands were prepared from the condensation of (+)-ketopinic acid with the corresponding
diamines and hydrazine under acidic conditions. When R-naphthyl acrylate was used as a Michael
acceptor, the reaction is complete within 20 min with high stereoselectivity and in reasonable
chemical yields.
The use of catalytic asymmetric reactions for the
synthesis of enantiomerically pure compounds has been
an ongoing effort of organic chemists. The coupling of an
R,â-unsaturated carbonyl/nitrile with an aldehyde (Bay-
lis-Hillman reaction) produces a useful functionalized
acrylate that allows for further functional group manipu-
lation.1 The reaction is mediated by a tertiary amine, and
1,4-diazabicyclo[2.2.2]octane (DABCO) is the most com-
monly used catalyst. Although the diastereoselective
Baylis-Hillman reaction has been shown to proceed, in
some cases, with high to excellent diastereoselectivities,2
the enantioselective variation of this reaction is less well
developed.3 Recently, Hatakeyama et al. reported that a
high to excellent enantiomeric excess can be achieved
when quinidine derivatives are used as chiral amine
catalysts.4 The use of a chiral Lewis acid to catalyze this
transformation is a common strategy. Aggarwal and co-
workers reported on the use of lanthanides and group
III metal triflates to accelerate the Baylis-Hillman
reaction.5 However, only 5% ee was obtained when these
metals were complexed with a broad range of oxygen-
rich chiral ligands. No practical levels of enantioselec-
tivity have yet been reported when a chiral Lewis acid
catalyst is used.
The stereocontrol elements for achieving enantioselec-
tive carbon-carbon bond formation rely on the proper
choice of metal and chiral ligands on suitable substrates.
The design and synthesis of a tunable chiral ligand
around a Lewis acid metal center constitutes an impor-
tant issue in the field of asymmetric synthesis.6 The
donor atoms of a ligand would be expected to moderate
the Lewis acidity of the metal and subsequently affect
the Lewis acid capability toward activation. On the other
hand, the structure of the starting substrate may also
play an important role (steric and stereoelectronic effects,
for example) in influencing the asymmetric outcome.
Thus, the importance of incorporating donor group
functionality into a ligand molecule is clear. Only a few
ligands, to the best of our knowledge, possess a free
carboxylic acid functionality.7 The carboxylic acid moiety
may serve as a good donor group by taking advantage of
the oxophilic nature of the metal. In continuation of our
research interest in the catalysis of such reactions, we
report here that practical levels of enantioselectivity can
be achieved using camphor-derived dimerized ligands
1-4 in the asymmetric Baylis-Hillman reaction.
* To whom correspondence should be addressed. Phone: 886(2)-
89315831. Fax: 886(2)29324249.
(1) For reviews of the Baylis-Hillman reaction, see: (a) Langer, P.
Angew. Chem., Int. Ed. 2000, 39, 3049. (b) Ciganek, E. Org. React.
1997, 51, 201. (c) Basavaiah, D.; Rao, D. P.; Hyma, R. S. Tetrahedron
1996, 52, 8001. (d) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988,
44, 4653.
(2) (a) Kundig, E. P.; Xu, L. H.; Romanens, P.; Bernardinelli, G.
Tetrahedron Lett. 1993, 34, 7049. (b) Yang, K.-S.; Chen, K. Org. Lett.
2000, 2, 729.
(3) (a) Brzezinski, L. J .; Rafel, S.; Leahy, J . W. J . Am. Chem. Soc.
1997, 119, 4317. (b) Barrett, A. G. M.; Cook, A. S.; Kamimura, A. J .
Chem. Soc. Chem. Commun. 1998, 2533. (c) Hayase, T.; Shibata, T.;
Soai, K.; Wakatsuki, Y. J . Chem. Soc., Chem. Commun. 1998, 1271.
(d) Oishi, T.; Oguri, H.; Hirama, M. Tetrahedron: Asymmetry 1995,
6, 1241. (e) Iwabuchi, Y.; Sugihara, T.; Esumi, T.; Hatakeyama, S.
Tetrahedron Lett. 2001, 42, 7867. (f) Iwabuchi, Y.; Furukawa, M.;
Esumi, T. Hatakeyama, S. Chem. Commun. 2001, 2030.
(4) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J .
Am. Chem. Soc. 1999, 121, 10219.
Resu lts a n d Discu ssion
Novel dimerized ligands 1-4 can be prepared from the
condensation of (+)-ketopinic acid with the corresponding
diamines and hydrazine under acidic conditions. Chiral
ligands 1 and 4 can be easily synthesized (69 and 88%,
respectively) using ethylenediamine and hydrazine in the
(6) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994.
(7) (a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New
York, 1993. (b) Barrett, A. G. M.; Kamimura, A. J . Chem. Soc., Chem
Commun. 1995, 1755. (c) Ishihara, K.; Kondo, S.; Yamamoto, H. J .
Org. Chem. 2000, 65, 9125. (d) Takasu, M.; Yamamoto, H. Synlett 1990,
194. (e) Sartor, D.; Saffrich, J .; Helmchen, G. Synlett 1990, 197. (f)
Corey, E. J .; Guzman-Perez, A.; Loh, T.-P. J . Am. Chem. Soc. 1994,
116, 3611. (g) Pan, J .-F.; Chen, K. J . Mol. Catal. A: Chem. 2001, 176,
19. (h) Yang, K.-S.; Chen, K. Org. Lett. 2002, 4, 1107.
(5) (a) Aggarwal, V. K.; Mereu, A.; Tarver, G. J .; McCague, R. J .
Org. Chem. 1998, 63, 7183. (b) Aggarwal, V. K.; Tarver, G. J .; McCague,
R. J . Chem. Soc., Chem. Commun. 1996, 2713.
10.1021/jo026318m CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/28/2002
J . Org. Chem. 2003, 68, 915-919
915

Yang et al.
TABLE 1. Rea ction of Ben za ld eh yd e a n d Meth yl
presence of acetic acid on a large scale. Treatment of
racemic trans-1,2-diaminocyclohexane with (+)-ketopinic
acid in refluxing CHCl3 for 36 h provides 2 (31%) and 3
(45%), respectively. These two diastereomeric ligands can
be separated by flash column chromatography, and the
absolute stereochemistry of 3 was further confirmed by
single-crystal X-ray analysis.
Acr yla tea
entry ligand Lewis acid yield (%)b % eec configurationd
The lanthanide metal triflates were screened with the
newly synthesized chiral ligands 1-4 using benzaldehyde
and methyl acrylate (A) as model probes.5 The catalytic
system used in this study has a number of appealing
features: (i) the molar ratio of chiral ligand to metal salts
was designated to be 2:1 so that optimum enantioselec-
tivity could be obtained under such conditions (deviation
in either direction led to a decrease in selectivity, data
not shown); (ii) a catalytic amount of catalyst (3 mol %
of metal) is sufficient for asymmetric induction; (iii) the
complexes are completely soluble in CH3CN, giving a
homogeneous solution in that ratio; and (iv) to prevent
the formation of potential amine-Lewis acid complexes
and therefore weaken the nucleophilic ability, a strictly
controlled amount of DABCO (10 equiv to the catalyst
or 30 mol % to substrate) was used. The use of chiral
ligand 1 (6 mol %) with Eu(OTf)3 (3 mol %) provided the
Baylis-Hillman adduct with no asymmetric induction,
while the use of Yb(OTf)3 resulted in 17% ee (entries 1
and 2). The enantioselectivity was significantly improved
when La(OTf)3 was used (entry 3). The La(OTf)3 cata-
lyzed Baylis-Hillman reaction was next studied using
other chiral ligands. The use of (S,S)-cyclohexyldiimino
ligand 2 provided the desired Baylis-Hillman adduct
with 67% ee, while the use of its diastereomeric ligand 3
provided the desired product with only 11% ee (entries 4
and 5). Diimine ligand 4 gave only polymerization
products (entry 6). The use of 1‚La(OTf)3 complexes
appears to be the best combination for the reaction and
was studied in great detail.
To further determine the feasibility of the catalytic
system, a range of activated alkenes with suitable
aldehydes were studied under optimized conditions. A
variety of acrylates with diverse steric, geometric, and
electronic properties were surveyed in this transforma-
tion. These included tert-butyl acrylate (B), phenyl acryl-
ate (C), benzyl acrylate (D), and R-naphthyl acrylate (E).9
The levels of asymmetric induction diminished appre-
ciably when aliphatic aldehydes were treated with me-
thylacrylate under the catalytic conditions employed
(Table 2, entries 1-3). Good selectivity was obtained with
low chemical yield when tert-butyl acrylate was used with
benzaldehyde (entry 5). Excellent chemical yield with
moderate stereoselectivity was obtained when phenyl
acrylate (C) was treated with benzaldehyde (entry 6).
1
2
3
4
5
6
1
1
1
2
3
4
Eu(OTf)3
Yb(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
81
72
75
70
71
0
0
17
84
67
11
S
S
S
S
S
a
Benzaldehyde (0.5 mmol) was reacted with methyl acrylate
A (0.5 mmol) in the presence of DABCO (30 mol %) and Lewis
acid catalyst (3 mol %) in CH3CN (2.6 mL) at room temperature
for 10 h. Isolated yield. c Determined by HPLC analysis using a
b
d
chiral column. Determined by comparison of optical rotation with
the literature value.8
TABLE 2. Rea ction of Acr yla tes A-E w ith Va r iou s
Ald eh yd es Ca ta lyzed by 1‚La (OTf)3 Com p lexesa
5
R1CHO
t
yield
entry acrylate
(R1))
(h) (%)b configuration (% ee)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
A
A
A
A
B
C
D
D
D
D
D
E
CH3
10
10
10
10
10
10
10
10
10
10
10
1/3 71
1/3 75
1/3 88
1/3 35
1/3 82
85
89
75
55
25
97
85
85
75
50
93
S
S
S
S
10
7
6
CH3CH2
(CH3)2CH
4-MeOC6H4
Ph
Ph
CH3
66
70
75
65
65
75
95
85
71e
70f
81
95
93
81
S
Sd
S
CH3CH2
Ph
S
Sd
S
4-MeOC6H4
4-NO2C6H4
c-C6H11
CH3CH2
Ph
4-MeOC6H4
4-NO2C6H4
Ph(CH2)2CH2 1/3 78
S
S
E
E
E
E
S
Sd
S
S
S
E
a
b
All reactions were carried out at room temperature. Isolated
yield. c Determined by HPLC analysis using a chiral column.
d
Absolute stereochemistry was determined by HPLC analysis
after conversion to known product 5A (R1 ) Ph, R2 ) CH3).8
Absolute stereochemistry of other products was assigned by
analogy. e % ee was determined by conversion to the corresponding
ester 5A (R1 ) c-C6H11, R2 ) CH3) for HPLC analysis. f % ee was
The stereoselectivity was remarkably enhanced when
benzyl acrylate (D) was reacted with various aldehydes.
A significant improvement in stereoselectivity was ob-
tained when aliphatic aldehydes were reacted with
benzyl acrylate (compare entry 1 with entry 2 and entry
7 with entry 8). The use of aromatic aldehydes with either
electron-donating or -deficient substituents on the ben-
zene ring gave high stereoselectivity (entries 10 and 11).
determined by conversion to the corresponding ester 5A (R1
CH3CH2, R2 ) CH3) for HPLC analysis.
)
The use of benzylacrylate to provide good to high levels
of stereoselectivity in the Baylis-Hillman products is
interesting. However, the reaction requires 10 h at room
temperature for completion. The mechanism of the Bay-
lis-Hillman reaction has been proposed, and the addition
(8) Drewes, S. E.; Emslie, N. D.; Field, J . S.; Kahn, A. A.; Ramesar,
N. Tetrahedron: Asymmetry 1992, 3, 255.
(9) Lee, W.-D.; Yang, K.-S.; Chen, K. Chem. Commun. 2001, 1612.
916 J . Org. Chem., Vol. 68, No. 3, 2003

Asymmetric Baylis-Hillman Reaction
Lewis acid. Studies of the origin of the rate acceleration,
as well as the stereochemical bias, are currently in
progress in our laboratory.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out in flame-
or oven-dried glassware under a positive pressure of nitrogen.
Air- and moisture-sensitive compounds were introduced by the
use of a cannula through a rubber septum. Most reagents were
commercially available and of synthetic grade. Tetrahydrofu-
ran was distilled from sodium/benzophenone ketyl. Dichlo-
romethane and toluene were dried over CaH2 and distilled
before use. Analytical thin-layer chromatography was per-
formed using silica gel 60F glass plates, and flash column
chromatography was performed using silica gel 60 (230-400
mesh). HRMS values were measured by either chemical
ionization (MS-CI) or electronic impact (MS-EI). Elemental
analyses were performed by Taipei Instrumentation Center,
F IGURE 1. Structures of camphor-derived chiral ligands 1-4.
1
College of Science (National Taiwan University). H and 13C
NMR spectra were recorded routinely in CDCl3 on a 200 or
400 MHz instrument. Enantiomeric ratios were determined
using a chiral column via HPLC analysis.
Gen er a l P r oced u r e for th e P r ep a r a tion of Diim in o
Ch ir a l Liga n d s 1-4. To a solution of (+)-ketopinic acid (10
g, 54.9 mmol) in CHCl3 (100 mL) were added ethylenediamine
(1.64 g, 27.4 mmol) and acetic acid (0.1 mL) at room temper-
ature. The resulting mixture was refluxed for 36 h and the
reaction then quenched with H2O (50 mL). The resulting
solution was extracted with CH2Cl2 (100 mL), and the layers
were separated. The organic layer was washed with brine (10
mL), dried (MgSO4), and concentrated. The crude product was
purified by silica gel using 4/1 EtOAc/CH2Cl2 as the eluent to
give 7.22 g (69%) of chiral ligand 1 as a white solid: 1H NMR
(CDCl3, 200 MHz) δ 3.65 (dd, J ) 15.0, 3.8 Hz, 4H), 2.56 (dd,
J ) 18.2, 3.6 Hz, 2H), 2.40 (td, J ) 12.2, 3.6 Hz, 2H), 2.15-
1.97 (m, 6H), 1.68 (td, J ) 12.8, 4.0 Hz, 2H), 1.43-1.30 (m,
2H,), 1.25 (s, 6H), 0.87 (s, 6H); 13C NMR (CDCl3, 50 MHz) δ
185.09, 173.21, 60.68, 50.78, 50.30, 43.86, 35.40, 31.62, 27.84,
20.07, 19.85; MS m/z (rel intensity) 388 (M+, 8), 373 (10), 319
(100), 163 (23), 148 (30); HRMS m/z 388.2336 (calcd for
F IGURE 2. Proposed mechanism of the enantioselective
Baylis-Hillman reaction.
of ammoniumenolate to an aldehyde was thought to be
the rate-determining step.5a Stabilization of the enolate
species would enhance the addition of DABCO to the
acrylate and therefore accelerate the reaction rates. On
the basis of this rationale and the results obtained above,
the larger steric volume of aromatic acrylate should
proceed at a higher reaction rate. To test this hypothesis,
R-naphthyl acrylate (E) was prepared and subjected to
the reaction conditions. To this end, treatment of the
cyclohexanecarboxaldehyde with R-naphthyl acrylate af-
forded the desired product in 71% yield in 20 min (entry
12). The enantioselectivity was determined to be 71% ee.
In the case of aromatic aldehydes, high levels of stereo-
selectivities were obtained under the same reaction
conditions (entries 14-16). Although a detailed under-
standing of the mechanism of this reaction remained
unclear, the enantiofacial bias may be rationalized as
follows. The hexadentate ligand binds to the metal atom,
followed by the coordination of the azaenolate and
aldehyde from the less hindered bottom side (Figure
2).5a,10 The azaenolate attacks the re face of the aldehyde
carbonyl sp2 carbon center leading to the desired (S)-
hydroxy configuration. The remarkable rate acceleration
can be attributed to the potential π-charge stabilization
of the intermediates between the naphthalene aromatic
system with the azaenolate.9 The same stereocontrol
elements of the catalyst are still operative for R-naphthyl
acrylate.
C
22H32N2O4 388.2362).
2: 1H NMR (CDCl3, 200 MHz) δ 3.45 (m, 2H), 2.52 (m, 2H),
2.36 (m, 2H), 2.11-1.98 (m, 6H), 1.81-1.67 (m, 4H,), 1.60-
1.24 (m, 6H), 1.22 (s, 6H), 0.86(s, 6H); 13C NMR (CDCl3, 50
MHz) δ 183.34, 173.13, 64.38, 60.19, 50.37, 43.68, 34.99, 31.77,
30.54, 27.84, 23.76, 20.04, 19.57; HRMS m/z 442.2834 (calcd
for C26H38N2O4 442.2832).
3: 1H NMR (CDCl3, 200 MHz) δ 3.43 (dd, J ) 5.2, 3.2 Hz,
2H), 2.61 (t, J ) 3.0 Hz, 1H), 2.54 (t, J ) 3.8 Hz, 1H), 2.35 (td,
J ) 12.1, 4.6 Hz, 2H), 2.11-1.92 (m, 6H), 1.83 (d, J ) 6.6 Hz,
2H), 1.65-1.27 (m, 10H), 1.25-1.24 (m, 2H), 1.23 (s, 6H), 0.83
(s, 6H); 13C NMR (CDCl3, 50 MHz) δ 183.24, 173.10, 64.33,
60.55, 49.31, 43.93, 34.93, 32.41, 31.07, 27.90, 23.85, 20.17,
20.06; MS m/z (rel intensity) 442 (M+, 7), 262 (35), 217 (50),
148 (45), 81 (100); HRMS m/z 442.2833 (calcd for C26H38N2O4
442.2832). Crystal data for 3 at 22 °C: C26H38N2O4, M )
442.59, tetragonal, P43212, a ) 7.8028(13) Å, c ) 40.282(4) Å,
V ) 2452.5 Å3, Z ) 4, λ ) 0.70930 Å, F(000) ) 960.56, Dc )
1.199 Mg/m3, µ ) 0.08 mm-1, 5242 reflections, 146 parameters,
R ) 0.051, Rw ) 0.067 for all data.
In conclusion, an effective chiral Lewis acid-catalyzed
asymmetric Baylis-Hillman reaction has been described.
Good to high enantioselectivities can be obtained using
3 mol % catalyst. In addition, when R-naphthyl acrylate
is used as a Michael acceptor, the reaction is complete
within 20 min, in reasonable chemical yields. This
represents the first practical demonstration that asym-
metric induction can be obtained by the aid of a chiral
4: Dichloromethane was used as a solvent for this reaction.
1H NMR (CDCl3, 200 MHz) δ 2.86 (t, J ) 3.6 Hz, 1H), 2.74 (t,
J ) 3.8 Hz, 1H), 2.53 (td, J ) 12.6, 4.8 Hz, 2H), 2.32-2.04 (m,
6H), 1.82 (td, J ) 9.0, 4.2 Hz, 2H), 1,45 (m, 2H), 1.29 (s, 6H),
0.98 (s, 6H); 13C NMR (CDCl3, 50 MHz) δ 181.90, 171.84, 60.99,
51.74, 44.03, 35.63, 31.65, 27.69, 20.01, 19.89; MS m/z (rel
intensity) 360 (M+, 10), 316 (40), 288 (60), 163 (75), 148 (100),
134 (80), 95 (90); HRMS m/z 360.2011 (calcd for C20H28N2O4
360.2049). Crystal data for 4 at 22 °C: C20H28N2O4, M )
360.45, monoclinic, C2, a ) 11.414(3) Å, b ) 7.580(4) Å, c )
21.887(3) Å, V ) 1865.4 Å3, Z ) 4, λ ) 0.70930 Å, F(000) )
(10) Hahn, F. E.; Mohr, J . Chem. Ber. 1990, 123, 481.
J . Org. Chem, Vol. 68, No. 3, 2003 917

Yang et al.
776.48, Dc ) 1.283 Mg/m3, µ ) 0.09 mm-1, 1812 reflections,
235 parameters, R ) 0.042, Rw ) 0.079 for all data.
(CDCl3, 50 MHz) δ 165.61, 143.52, 141.66, 128.22 (×2), 127.55,
126.57 (×2), 124.93, 81.40, 73.15, 27.72 (x3). HPLC condition:
10/90 2-propanol/hexane (0.5 mL/min), tR ) 8.1 min (S) and
10.4 min (R).
Gen er a l P r oced u r e for th e Asym m etr ic Ba ylis-Hill-
m a n Rea ction . To a solution of chiral ligand 1 (12 mg, 0.03
mmol) in CH3CN (2.6 mL) was added La(OTf)3 (9 mg, 0.015
mmol) at room temperature under an N2 atmosphere. This was
stirred for 10 min, and benzaldehyde (54 mg, 0.51 mmol),
R-naphthyl acrylate (0.10 g, 0.51 mmol), and DABCO (17 mg,
0.15 mmol) were added sequentially. The resulting mixture
was stirred for 20 min and the reaction quenched with H2O (5
mL). The mixture was extracted with CH2Cl2 (10 mL), and
the layers were separated. The organic layer was washed with
brine (10 mL), dried (MgSO4), and concentrated. The crude
product was purified by silica gel using 8/1 hexane/EtOAc as
an eluent to give 0.13 g (88%) of 5E (R1) Ph) as a white solid.
The enantiomeric ratios were determined by HPLC analyses
using a chiral column.
Met h yl (S)-3-H yd r oxy-3-p h en yl-2-m et h ylen ep r op a n -
oa te. Colorless oil (84% ee): [R]D ) +93.3° (c 1.0, CHCl3); lit.8
[R]D ) -111.1° (c 1.11, MeOH) for the (R)-enantiomer. 1H NMR
(CDCl3, 200 MHz) δ 7.38-7.26 (m, 5H), 6.32 (d, J ) 1.2 Hz,
1H), 5.85 (d, J ) 1.2 Hz, 1H), 5.54 (s, 1H), 3.69 (1, 3H), 3.13
(br, 1H); 13C NMR (CDCl3, 50 MHz) δ 166.71, 142.06, 141.32,
128.33, 127.72, 126.57, 125.85, 72.89, 51.72; MS m/z (rel
intensity) 192 (M+, 20), 191 (30), 160 (45), 105 (100), 77 (40);
HRMS m/z 192.0777 (calcd for C11H12O3 192.0786). HPLC
condition: 20/80 2-propanol/hexane (0.5 mL/min), tR ) 13.3
min (S) and 15.3 min (R).
Meth yl (S)-3-Hyd r oxy-2-m eth ylen ebu ta n oa te. Colorless
oil (10% ee): 1H NMR (CDCl3, 200 MHz) δ 6.11 (d, J ) 1.0
Hz, 1H), 5.76 (d, J ) 1.0 Hz, 1H), 4.54 (q, J ) 6.4 Hz, 1H),
3.67 (s, 3H), 3.16 (br, 1H), 1.38 (d, J ) 6.4 Hz, 3H); 13C NMR
(CDCl3, 50 MHz) δ 166.94, 143.73, 123.84, 66.46, 51.59, 22.03;
MS m/z (rel intensity) 129 (M+, 5), 115 (65), 87 (80), 83 (100),
55 (55). HPLC condition: 2/98 2-propanol/hexane (0.8 mL/min),
tR ) 17.3 min (R) and 19.4 min (S).
Meth yl (S)-3-Hyd r oxy-2-m eth ylen ep en ta n oa te. Color-
less oil (7% ee): 1H NMR (CDCl3, 200 MHz) δ 6.15 (d, J ) 1.0
Hz, 1H), 5.74 (d, J ) 1.0 Hz, 1H), 4.27 (t, J ) 6.2 Hz, 1H),
3.69 (s, 3H), 2.91 (br, 1H), 1.68-1.46 (qd, J ) 7.4, 6.2 Hz, 2H),
0.86 (t, J ) 7.4 Hz, 3H); 13C NMR (CDCl3, 50 MHz) δ 166.97,
142.41, 124.75, 72.16, 51.54, 28.86, 9.65. HPLC condition: 2/98
2-propanol/hexane (0.5 mL/min), tR ) 20.7 min (R) and 23.2
min (S).
P h en yl (S)-3-H yd r oxy-3-p h en yl-2-m et h ylen ep r op a n -
oa te. Colorless oil (75% ee): 1H NMR (CDCl3, 200 MHz) δ
7.49-7.21 (m, 8H), 7.05-7.00 (m, 2H), 6.62 (d, J ) 1.0 Hz,
1H), 6.11 (d, J ) 1.0 Hz, 1H), 5.68 (s, 1H), 3.01 (br, 1H); 13C
NMR (CDCl3, 50 MHz) δ 164.70, 150.34, 141.89, 141.19, 129.34
(×2), 128.45 (×2), 127.92, 127.21 (×2), 126.72, 125.89, 121.39
(×2), 72.77; MS m/z (rel intensity) 254 (M+, 5), 161 (100), 133
(45), 117 (95), 94 (95), 77 (45). HRMS m/z 254.0921 (calcd for
C16H14O3 254.0943). HPLC condition: 20/80 2-propanol/hexane
(0.5 mL/min), tR ) 15.5 min (R) and 19.5 min (S).
Ben zyl (S)-3-Hyd r oxy-2-m eth ylen ebu ta n oa te. Colorless
oil (65% ee): 1H NMR (CDCl3, 200 MHz) δ 7.39-7.26 (m, 5H),
6.27 (s, 1H), 5.86 (s, 1H), 5.22 (s, 2H), 4.65 (q, J ) 6.4 Hz,
1H), 2.77 (br, 1H), 1.38 (d, J ) 6.4 Hz, 3H); 13C NMR (CDCl3,
50 MHz) δ 166.43, 143.61, 135.66, 128.60 (×2), 128.31, 128.09
(×2), 124.41, 66.88, 66.47, 22.00; MS m/z (rel intensity) 206
(M+, 5), 143 (15), 107 (20), 91 (95), 82 (100), 54 (55). HRMS
m/z 206.0917 (calcd for C12H14O3 206.0943). HPLC condition:
2/98 2-propanol/hexane (0.5 mL/min), tR ) 25.0 min (R) and
27.6 min (S).
Ben zyl (S)-3-Hyd r oxy-2-m eth ylen ep en ta n oa te. Color-
less oil (65% ee): 1H NMR (CDCl3, 200 MHz) δ 7.37-7.29 (m,
5H), 6.27 (d, J ) 1.0 Hz, 1H), 5.84 (d, J ) 1.0 Hz, 1H), 5.19 (s,
2H), 4.40 (t, J ) 6.2 Hz, 1H), 3.19 (s, 1H), 1.67 (qd, J ) 7.4,
6.2 Hz, 2H), 0.93 (t, J ) 7.4 Hz, 3H); 13C NMR (CDCl3, 50
MHz) δ 166.36, 142.30, 135.66, 128.56 (×2), 128.25, 128.02
(×2), 125.29, 72.66, 66.40, 28.97, 9.88; MS m/z (rel intensity)
220 (M+, 5), 181 (10), 173 (10), 96 (55), 91 (100), 68 (20). HRMS
m/z 220.1088 (calcd for C13H16O3 220.1099). HPLC condition:
2/98 2-propanol/hexane (0.8 mL/min), tR ) 23.7 min (R) and
26.1 min (S).
Ben zyl (S)-3-Hydr oxy-3-ph en yl-2-m eth ylen epr opan oate.
Colorless oil (75% ee): 1H NMR (CDCl3, 200 MHz) δ 7.39-
7.23 (m, 10H), 6.42 (s, 1H), 5.91 (d, J ) 1.0 Hz, 1H), 5.59 (s,
1H), 5.15 (s, 2H), 2.95 (br, 1H); 13C NMR (CDCl3, 50 MHz) δ
166.06, 142.07, 141.32, 135.50, 128.49 (×2), 128.40 (×2),
128.21, 128.01 (×2), 127.80, 126.67, 126.22, 73.00, 66.50; MS
m/z (rel intensity) 268 (M+, 2), 177 (100), 162 (10), 159 (20),
105 (10), 91 (10). HPLC condition: 20/80 2-propanol/hexane
(0.5 mL/min), tR ) 15.1 min (S) and 16.1 min (R).
Meth yl (S)-3-Hyd r oxy-3-(p-m eth oxyp h en yl)-2-m eth yl-
en ep r op a n oa te. White solid (66% ee): 1H NMR (CDCl3, 200
MHz) δ 7.28 (dd, J ) 9.0, 2.2 Hz, 2H), 6.86 (dd, J ) 9.0, 2.2
Hz, 2H), 6.29 (d, J ) 1.0 Hz, 1H), 5.85 (d, J ) 1.2 Hz, 1H),
5.49 (d, J ) 4.8 Hz, 1H), 3.76 (s, 3H), 3.68 (s, 3H), 3.14 (d, J
) 5.0 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 166.73, 159.17,
142.26, 133.52, 127.89 (×2), 125.32, 113.72 (×2), 72.43, 55.06,
51.71; MS m/z (rel intensity) 222 (M+, 10), 143 (100), 115 (40),
105 (35), 91 (60), 83 (30); HRMS m/z 222.0887 (calcd for
Ben zyl (S)-3-Hyd r oxy-3-(p-m eth oxyp h en yl)-2-m eth yl-
en ep r op a n oa te. White solid (95% ee): 1H NMR (CDCl3, 200
MHz) δ 7.43-7.21 (m, 7H), 6.90-6.83 (m, 2H), 6.39 (d, J )
1.0 Hz, 1H), 5.90 (d, J ) 1.0 Hz, 1H), 5.55 (s, 1H), 5.14 (s,
2H), 3.80 (s, 3H), 2.70 (br, 1H); 13C NMR (CDCl3, 50 MHz) δ
166.15, 159.31, 142.32, 135.60, 133.52, 128.51 (×2), 128.22
(×2), 128.01 (×2), 125.76 (×2), 113.84 (×2), 72.62, 66.47, 55.15;
MS m/z (rel intensity) 298 (M+, 5), 207 (85), 189 (75), 135 (100),
121 (35), 99 (20), 91 (80). HRMS m/z 298.1155 (calcd for
C18H18O4 298.1205). HPLC condition: 20/80 2-propanol/hexane
(0.7 mL/min), tR ) 13.5 min (S) and 16.5 min (R).
Ben zyl (S)-3-Hyd r oxy-3-(p-n itr op h en yl)-2-m eth ylen e-
p r op a n oa te. White solid (85% ee): 1H NMR (CDCl3, 200
MHz) δ 8.12 (d, J ) 8.6 Hz, 2H), 7.51 (d, J ) 8.6 Hz, 2H),
7.34-7.22 (m, 5H), 6.44 (s, 1H), 5.94 (d, J ) 1.0 Hz, 1H), 5.63
(s, 1H), 5.13 (s, 2H), 3.32 (br, 1H); 13C NMR (CDCl3, 50 MHz)
δ 165.61, 148.67, 147.31, 141.16, 135.11, 128.51 (×2), 128.40,
128.10 (×2), 127.37 (×2), 127.22, 123.46 (×2), 72.22, 66.77;
MS m/z (rel intensity) 313 (M+, 3), 222 (15), 204 (35), 189 (85),
161 (80), 150 (25), 91 (100), 77 (15), 65 (15). HRMS m/z
313.0961 (calcd for C17H15NO5 313.0950). Anal. Calcd for
C
12H14O4 222.0892). Anal. Calcd for C12H14O4: C, 64.85; H,
6.35. Found: C, 64.80; H, 6.34. HPLC condition: 20/80
2-propanol/hexane (0.7 mL/min), tR ) 11.2 min (S) and 14.1
min (R).
Meth yl (S)-3-Hyd r oxy-3-(p-n itr op h en yl)-2-m eth ylen e-
p r op a n oa te. White solid (17% ee): 1H NMR (CDCl3, 200
MHz) δ 8.16 (d, J ) 8.8 Hz, 2H), 7.55 (d, J ) 8.8 Hz, 2H), 6.37
(d, J ) 1.0 Hz, 1H), 5.88 (d, J ) 1.0 Hz, 1H), 5.61 (s, 1H), 3.71
(s, 3H), 3.12 (br, 1H); 13C NMR (CDCl3, 50 MHz) δ 166.43,
148.72, 147.48, 141.09, 127.37, 127.16, 123.58, 72.51, 52.09;
MS m/z (rel intensity) 237 (M+, 20), 220 (50), 205 (40), 177
(100), 150 (85), 115 (20), 77 (20), 55 (20). HRMS m/z 237.0637
(calcd for C11H11NO5 237.0637). HPLC condition: 20/80 2-pro-
panol/hexane (0.7 mL/min), tR ) 12.7 min (S) and 13.8 min
(R).
C
17H15NO5: C, 65.17; H, 4.83; N, 4.47. Found: C, 64.95; H,
4.70; N, 4.47. HPLC condition: 20/80 2-propanol/hexane (0.7
mL/min), tR ) 16.8 min (S) and 19.0 min (R).
ter t-Bu t yl (S)-3-H yd r oxy-3-p h en yl-2-m et h ylen ep r o-
p a n oa te. White solid (70% ee): 1H NMR (CDCl3, 200 MHz) δ
7.35-7.25 (m, 5H), 6.24 (d, J ) 1.0 Hz, 1H), 5.75 (d, J ) 1.0
Hz, 1H), 5.47 (s, 1H), 3.37 (br, 1H), 1.38 (s, 9H); 13C NMR
R-Na p h th yl (S)-3-Cycloh exyl-3-h yd r oxy-2-m eth ylen e-
p r op a n oa te. Colorless oil (71% ee): 1H NMR (CDCl3, 200
MHz) δ 7.92-7.76 (m, 3H), 7.57-7.46 (m, 3H), 7.28 (d, J )
9.2 Hz, 1H), 6.73 (d, J ) 1.0 Hz, 1H), 6.05 (d, J ) 1.0 Hz, 1H),
918 J . Org. Chem., Vol. 68, No. 3, 2003

Asymmetric Baylis-Hillman Reaction
4.27 (d, J ) 7.0 Hz, 1H), 2.30 (br, 1H), 2.07-2.00 (m, 1H),
1.84-1.67 (m, 5H), 1.33-1.02 (m, 5H); 13C NMR (CDCl3, 50
MHz) δ 165.29, 146.40, 140.84, 134.73, 128.16, 128.04, 126.66,
126.57, 126.26, 125.43, 121.03 (×2), 118.19, 77.18, 45.47, 30.04,
28.22, 26.28, 26.05, 25.86; MS m/z (rel intensity) 310 (M+, 2),
144 (100), 115 (20), 83 (10), 55 (15). HRMS m/z 310.1575 (calcd
for C20H22O3 310.1569). HPLC condition for methyl (S)-3-
hydroxy-3-cyclohexyl-2-methylenepropanoate: 2/98 2-propanol/
hexane (0.5 mL/min), tR ) 20.4 min (R) and 22.5 min (S).
R-Naph th yl (S)-3-Hydr oxy-2-m eth ylen epen tan oate. Col-
orless oil (70% ee): [R]D ) +97.6° (c 1.0, CHCl3); 1H NMR
(CDCl3, 200 MHz) δ 7.92-7.76 (m, 3H), 7.55-7.45 (m, 3H),
7.30 (dd, J ) 7.6, 1.2 Hz, 1H), 6.71 (d, J ) 1.0 Hz, 1H), 6.12
(d, J ) 1.0 Hz, 1H), 4.54 (q, J ) 6.4 Hz, 1H), 2.45 (br, 1H),
1.85 (qd, J ) 7.4, 6.4 Hz, 2H), 1.05 (t, J ) 7.4 Hz, 3H); 13C
NMR (CDCl3, 50 MHz) δ 165.15, 146.41, 141.97, 134.70,
128.12, 126.95, 126.84, 126.63, 126.54, 126.22, 125.38, 121.03,
118.15, 72.80, 29.12, 10.02; MS m/z (rel intensity) 256 (M+,
3), 227 (5), 144 (100), 115 (10), 95 (5), 83 (5), 55 (10). HRMS
m/z 256.1050 (calcd for C16H16O3 256.1099). HPLC condition
for methyl (S)-3-hydroxy-2-methylenepentanoate: 2/98 2-pro-
panol/hexane (0.5 mL/min), tR ) 20.7 min (R) and 23.2 min
(S).
R-Na p h th yl (S)-3-Hyd r oxy-3-p h en yl-2-m eth ylen ep r o-
p a n oa te. White solid (81% ee): 1H NMR (CDCl3, 200 MHz) δ
7.86 (d, J ) 8.0 Hz, 1H) 7.80 (d, J ) 8.0 Hz, 1H), 7.58-7.35
(m, 9H), 7.20 (dd, J ) 7.6, 0.6 Hz, 1H), 6.78 (d, J ) 1.0 Hz,
1H), 6.22 (d, J ) 1.0 Hz, 1H), 5.78 (s, 1H), 3.15 (br, 1H); 13C
NMR (CDCl3, 50 MHz) δ 164.94, 146.31, 141.77, 141.15,
134.62, 128.71 (×2), 128.18, 127.99, 127.60, 126.90 (×2),
126.69, 126.52, 126.48, 126.26, 125.32, 121.05, 118.06, 73.21;
MS m/z (rel intensity) 304 (M+, 5), 286 (3), 161 (5), 144 (100),
115 (75), 105 (10), 77 (15), 55 (5). HRMS m/z 304.1144 (calcd
for C20H16O3 304.1099). Anal. Calcd for C20H16O3: C, 78.93;
H, 5.30. Found: C, 78.82; H, 5.20. HPLC condition: 20/80
2-propanol/hexane (0.6 mL/min), tR ) 25.4 min (S) and 29.1
min (R).
115 (60), 77 (10). HRMS m/z 318.1230 (calcd for C21H18O3
318.1256). HPLC condition: 10/90 2-propanol/hexane (0.8 mL/
min), tR ) 21.3 min (S) and 25.9 min (R).
R-Na p h th yl (S)-3-Hyd r oxy-3-(p-n itr op h en yl)-2-m eth -
ylen ep r op a n oa te. White solid (93% ee): 1H NMR (CDCl3,
200 MHz) δ 7.86 (dd, J ) 9.0, 2.0 Hz, 2H), 7.86 (d, J ) 8.8 Hz,
1H), 7.65 (d, J ) 8.8 Hz, 1H), 7.56-7.43 (m, 6H), 7.16 (dd, J
) 7.6, 1.0 Hz, 1H), 6.83 (d, J ) 1.0 Hz, 1H), 6.20 (d, J ) 1.0
Hz, 1H), 5.80 (s, 1H), 3.30 (br, 1H); 13C NMR (CDCl3, 50 MHz)
δ 164.57, 148.43, 147.54, 146.05, 140.89, 134.61, 128.65,
128.12, 127.55, 126.60, 126.43, 125.31, 123.69, 120.67, 117.98,
72.24; MS m/z (rel intensity) 349 (M+, 3), 189 (3), 176 (5), 160
(5), 144 (100), 115 (30), 77 (5), 55 (5). HRMS m/z 349.0951
(calcd for C20H15NO5 349.0950). HPLC condition: 20/80 2-pro-
panol/hexane (0.8 mL/min), tR ) 22.2 min (S) and 31.9 min
(R).
R-Na p h th yl (S)-3-Hyd r oxy-5-p h en yl-2-m eth ylen ep en -
ta n oa te. Colorless oil (81% ee): 1H NMR (CDCl3, 200 MHz) δ
7.93-7.77 (m, 3H), 7.58-7.46 (m, 3H), 7.36-7.18 (m, 6H), 6.73
(d, J ) 1.0 Hz, 1H), 6.15 (d, J ) 1.0 Hz, 1H), 4.63 (dd, J ) 7.6,
4.8 Hz, 1H), 3.01-2.75 (m, 2H), 2.72 (br, 1H), 2.21-2.07 (m,
2H); 13C NMR (CDCl3, 50 MHz) δ 165.15, 146.38, 142.09,
141.56, 134.72, 128.54, 128.51, 128.15, 127.05, 126.83, 126.67,
126.58, 126.29, 126.01, 125.41, 121.03, 118.16, 70.90, 37.70,
32.05; MS m/z (rel intensity) 332 (M+, 3), 227 (5), 171 (10),
144 (100), 115 (55), 91 (90), 77 (5), 65 (5), 55 (5). HRMS m/z
332.1389 (calcd for C22H20O3 332.1412). HPLC condition: 10/
90 2-propanol/hexane (0.6 mL/min), tR ) 41.5 min (R) and 53.7
min (S).
Ack n ow led gm en t. This work is supported by the
National Science Council of the Republic of China and
the National Taiwan Normal University (ORD 91-2).
The X-ray crystal data, collected and processed by Taipei
Instrumentation Center, College of Science (National
Taiwan University), and Professor C.-H. Ueng (National
Taiwan Normal University), are gratefully acknowl-
edged.
R-Na p h th yl (S)-3-Hyd r oxy-3-(p-m eth oxyp h en yl)-2-m e-
th ylen ep r op a n oa te. White solid (95% ee): 1H NMR (CDCl3,
200 MHz) δ 7.83 (d, J ) 7.4 Hz, 1H), 7.73 (d, J ) 8.4 Hz, 1H),
7.52-7.35 (m, 6H), 7.16 (dd, J ) 7.4, 0.8 Hz, 1H), 6.93 (dd, J
) 8.8, 2.2 Hz, 2H), 6.76 (d, J ) 1.0 Hz, 1H), 6.20 (d, J ) 1.0
Hz, 1H), 5.75 (s, 1H), 3.83 (s, 3H), 2.82 (br, 1H); 13C NMR
(CDCl3, 50 MHz) δ 164.98, 159.61, 146.38, 142.65, 133.38,
128.28 (×2), 127.99, 127.07, 126.73, 126.48 (×2), 126.23,
125.35, 121.12, 118.09, 114.10 (×2), 72.75, 55.29; MS m/z (rel
intensity) 318 (M+, 20), 272 (30), 191 (100), 163 (20), 144 (90),
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
(1H and 13C NMR) for all new compounds and crystallographic
information including experimental details, bond lengths, bond
angles, and ORTEP diagrams for ligands 3 and 4. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O026318M
J . Org. Chem, Vol. 68, No. 3, 2003 919