Lewis base catalyzed enantioselective allylic hydroxylation of Morita-Baylis-Hillman carbonates with water

Article abstract of DOI:10.1021/jo201096e

A Lewis base catalyzed allylic hydroxylation of Morita-Baylis-Hillman (MBH) carbonates has been developed. Various chiral MBH alcohols can be synthesized in high yields (up to 99%) and excellent enantioselectivities (up to 94% ee). This is the first report using water as a nucleophile in asymmetric organocatalysis. The nucleophilic role of water has been verified using ¹⁸O-labeling experiments.

Full text of DOI:10.1021/jo201096e

NOTE
pubs.acs.org/joc
Lewis Base Catalyzed Enantioselective Allylic Hydroxylation
of MoritaÀBaylisÀHillman Carbonates with Water
Bo Zhu,† Lin Yan,† Yuanhang Pan,‡ Richmond Lee,§ Hongjun Liu,‡ Zhiqiang Han,† Kuo-Wei Huang,§
Choon-Hong Tan,*,†,‡ and Zhiyong Jiang*,†
†Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Kaifeng, Henan 475004,
People’s Republic of China
‡Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
§KAUST Catalysis Center and Division of Chemical and Life Sciences and Engineering, King Abdullah University of Science and
Technology, Thuwal, Kingdom of Saudi Arabia, 23955-6900
S Supporting Information
b
ABSTRACT: A Lewis base catalyzed allylic hydroxylation of MoritaÀ
BaylisÀHillman (MBH) carbonates has been developed. Various chiral MBH
alcohols can be synthesized in high yields (up to 99%) and excellent enantios-
electivities (up to 94% ee). This is the first report using water as a nucleophile in
asymmetric organocatalysis. The nucleophilic role of water has been verified
using 18O-labeling experiments.
BH alcohols, containing condensed functional groups, are
valuable intermediates for organic synthesis.1,2 Many im-
Scheme 1. Postulated Mechanisms for the Synthesis of MBH
Alcohols from MBH Carbonates and Water
M
portant biologically active compounds and natural products have
been reported to be prepared from MBH alcohols.3 The most
efficient and direct protocol of preparing chiral MBH alcohols is
via the well-known asymmetric MoritaÀBaylisÀHillman (MBH)
reaction between activated terminal alkenes and aldehydes.1À4
Other processes have also been developed, such as NozakiÀ
HiyamaÀKishi reaction from the addition of organochromium-
(III) vinylation reagents to carbonyl compounds,5À7 carbonyl
reduction of R-methylene ketones,8À11 aldol oxidative deseleni-
zation cascade reaction,12 acylative kinetic resolution of racemic
MBH alcohols,13 and a two-step protocol of allylic alkylation
of MBH carbonates with oxa donors.14À17 In 2002, Kim et al.
presented an asymmetric hydroxylation of MBH acetates with
moderate to excellent enantioselectivities in the presence of a
Lewis base catalyst. This is a kinetic resolution route from the
hydrolysis with NaHCO3 and using water as a surrogate.18 Despite
the low reaction rate and low yield (of less than 50%), this
methodology presents a significant improvement for the synthesis
of MBH alcohols. Considering the reaction mechanisms of
Kim’s18 and allylic alkylations of MBH adducts,19À32 we postulate
that, in the presence of a Lewis base catalyst, tert-butoxide is
derived from the expulsion of MBH carbonate, which then
generates hydroxide from water (pathway A, Scheme 1). Subse-
quently, under suitable reaction conditions, the hydroxide anion
would act as a nucleophile and attack the intermediate to give the
desired MBH alcohol (pathway A, Scheme 1). At the same time,
the formation of hydrogen carbonate ion which acts as a water
surrogate also cannot be excluded (pathway B, Scheme 1).18,33
Preliminary studies with the model substrate MBH carbonate
1a were carried out. In the presence of 10 mol % of PPh3,
imidazole, DBU, DMAP, or TMG, no desired product, MBH
alcohol 2a, was obtained. However, when 10 mol % of DABCO
was used, the reaction completed with good yield in 16 h
(Table 1, entry 1). Further optimization with DMF allowed
the reaction to achieve 96% yield within 6 h (Table 1, entry 2).
However, no product was formed when protic solvent methanol
was used (Table 1, entry 3). A plausible reason could be that the
nucleophile’s reactivity is diminished due to intermolecular
hydrogen bonding between the nucleophile and methanol.
When the concentration of water (Table 1, entries 5À9) was
varied, the optimal condition was found be 2 equiv (Table 1,
entry 6). However, no reaction was observed when the concen-
tration of water is significantly increased to the ratio of 1:1 DMF/
H2O (Table 1, entry 9).
Received: May 27, 2011
Published: July 13, 2011
r
2011 American Chemical Society
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|

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NOTE
Table 1. Investigating Reactivity with Various Solventsa
Table 2. Synthesis of MBH Alcohols from the Reactions
between MBH Carbonates 1bÀn and Water Catalyzed by
DABCOa
entry
solventb
additive
time (h)
yield (%)c
entry
R1
1
R2
2
time (h) yield (%)b
1
2
3
4
5
6
7
8
9
acetonitrile
DMF
16
91
6
96
1
2
p-NO2Ph
m-NO2Ph
p-FPh
1b
1c
1d
1e
1f
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOtBu
2b
2c
2d
2e
2f
0.5
0.5
0.4
0.4
0.6
1.5
1.0
6.0
7.0
6.0
4.0
5.0
7.5
99
99
99
99
94
99
99
82
90
60
80
67
76
60c
methanol
DMF
24
NRd
36e
74e
96e,f
78e
66e
0.25
0.25
0.25
0.25
0.25
24
3
DMF
H2O/1.0 equiv
H2O/2.0 equiv
H2O/5.0 equiv
H2O/10 equiv
H2Og
4
p-BrPh
DMF
5
o-ClPh
DMF
6
p-CH3Ph
2-naphthyl
1g
1h
2g
2h
2i
DMF
7
DMF
NRd,e
8
p-CH3OPh 1i
a Reactions were performed with 0.05 mmol of 1a and 0.005 mmol of
DABCO in 0.5 mL of solvent. b Dried and distilled before used. c Isolated
yields. d NR = no reaction. e Conversion, determined by HPLC analysis.
9
3-thienyl
2-furyl
Ph
1j
1k
1l
2j
10
11
12
13
14
2k
2l
f Isolated yield = 99%, after 1 h, 1 mmol scale. DMF (0.25 mL) and
g
H2O (0.25 mL) were used as solvent.
Ph
1m CN
2m
Ph
1n
1o
PO(OEt)2 2n
Et
COOMe 2o
12
With a set of optimized reaction conditions on hand (10 mol
% of DABCO as catalyst, 2.0 equiv of H2O as additive, in DMF at
room temperature), we then investigated the scope of the achiral
reaction. Different MBH alcohols 2bÀ2l could be efficiently
synthesized from MBH carbonates 1bÀ1l derived from aromatic
aldehydes and alkyl acrylates (Table 2, entries 1À11). In general,
the reactions were complete in 7 h with good to excellent yields
with the exception of 1k. Electronic effect and its influence on
reactivity are tuned in favor for electron-withdrawing MBH
carbonates 1bÀ1f (Table 2, entries 1À5). Less reactive MBH
carbonates (1m,1n) with acrylonitrile and diethyl vinylphospho-
nate moieties instead of esters were also investigated, and the
desired MBH alcohols 2m,2n could be achieved with moderate
yields (Table 2, entries 12 and 13). Aliphatic MBH carbonate 1o
was also under investigation. The reaction was finished within
0.5 h at room temperature. However, the yield of aliphatic MBH
alcohol 2o was less than 30%; an unknown compound was
detected as the major product. Finally, 60% yield of 2o was
obtained after 12 h when the reaction was conducted at À10 °C
(Table 2, entry 14).
Another important class of MBH carbonates 3aÀc, in which
the alkenes are activated by cyclic ketones, was also investigated.
The corresponding MBH alcohols 4aÀc were prepared
(Scheme 2). Unfortunately, no product was formed under our
established reaction conditions. It was found, after some at-
tempts, that using 20 mol % of DMAP in the place of DABCO,
gave moderate yields.
Next, we endeavored to prepare enantiopure MBH alcohols
with our established protocol. Carbonate 1a was subjected to
allylic hydroxylation with 2 equiv of H2O in DMF via screening
with a series of Cinchona alkaloids as Lewis base organocatalysts
(Table 3, entries 1À5).34À40 The best enantioselectivity with
85% ee was achieved for (DHQD)2AQN with adduct 5a
(Table 3, entry 5). The ee was improved from 85 to 87% by
replacing DMF with N,N-dimethylacetamide (DMAC) for the
similar substrate (Table 3, entry 6). Next, several additives
(Table 3, entries 7À14) were screened and it was found that
the addition of pyridine decreased ee to 36% despite making the
a At 0.1 mmol scale in 1.0 mL of DMF. b Isolated yields. c The reaction
was conducted at À10 °C.
Scheme 2. Synthesis of MBH Alcohols Containing Cyclic
Ketones (0.1 mmol Scale in 1.0 mL of DMF; Isolated Yield)
reaction faster (Table 3, entry 7).27,41 Since inorganic fluorides
were often used as additives to improve reactions,42 we examined
several fluorides as additives (Table 3, entries 8À12). The results
show that alkaline earth fluorides, especially CaF2 (Table 3, entry
10), are effective for enhancing the enantioselectivity. Finally,
when 2.0 equiv of CaF2 was used, the enantioselectivity im-
proved to 91% (Table 3, entry 14).43
We expanded the reaction scope to synthesize other chiral
MBH alcohols (Table 4). All of the reactions proceeded
smoothly in good to excellent yields (up to 95%) and ee values
(up to 94%). We found that the optimized condition for 1a was
not completely suitable for other MBH carbonates. The en-
antioselectivities were influenced by ratios of H2O and CaF2 as
well as the reaction temperature. Five equivalents of H2O and
CaF2 at À10 °C was required for the synthesis of 5bÀg, whereas
0 °C was essential to 5i,j using the same amount of additives.
Meanwhile, the MBH alcohols 5cÀf and 5hÀj with meta-
substituted groups on the phenyl rings led to higher enantios-
electivities. This synthetic protocol was also applicable to less
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NOTE
Table 3. Investigation of Reaction Conditions To Synthesize
Chiral MBH Alcohol 5a from MBH Carbonate 1a and H2Oa
activated aldehydes (e.g., anisaldehydes) and deactivated Mi-
chael acceptors, for example, acrylonitrile,44 which are generally
poor partners from the viewpoint of efficiency to the established
asymmetric MBH reactions.1À4 Unfortunately, not all of the
substituted aromatic chiral MBH alcohols could achieve excellent
enantioselectivities under the established reaction conditions.44
We believe that, with further investigations, satisfactory enantios-
electivities of different MBH carbonates could be achieved.
To shed light on the role of water in allylic alkylation of MBH
carbonates, isotope labeling experiments were conducted
(Scheme 3). When H218O was used in the optimized achiral
reaction conditions with MBH carbonate 1a, it was observed that
high yields of MBH alcohols [18O]-2a were obtained with high
18O incorporation level.45 Next, 18O-labeled MBH carbonate
[18O]-1a, which was prepared from [18O]-2a, was subjected in
the same reaction condition with 2 equiv of H2O. MBH alcohol
2a was obtained without the determination of [18O]-2a
(Scheme 3, eq 1). Thus, it is obvious that water acts as a
nucleophile in this reaction, and the proposed pathway A is
favored (Scheme 1, pathway A). The nucleophilic role of
water in the asymmetric reaction was also confirmed
(Scheme 3, eq 2).46
In conclusion, we have developed a practical allylic hydroxyla-
tion of MBH carbonates with H2O in the presence of Lewis basic
catalysts such as DABCO, DMAP, or Cinchona alkaloids. From
this protocol, various synthetically valuable achiral MBH alcohols
and chiral MBH alcohols were achieved directly in high yields
and excellentenantioselectivities. Thisisthefirst report on organo-
catalytic asymmetric synthesis employing water as a nucleo-
phile. We believe this work should serve to promote water as
nucleophile in other CÀO bond construction reactions. We
also envisage opportunities to employ this chemistry for the
facile, single-step synthesis of 18O-labeled drugs or drug
time
(h)
yield
(%)b
ee
(%)c
entry
catalyst
solvent additive
1
2
(DHQD)2PHAL DMF
60
60
60
60
48
72
24
72
72
72
72
72
72
72
45
60
77
56
94
88
63
55
74
88
62
80
40
86
81
À42
À44
77
(DHQ)2PYR
DMF
3
(DHQ)2AQN
DMF
4
(DHQD)2PYR
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
(DHQD)2AQN
DMF
5
DMF
85d
6
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
DMAC
87
36
87
89
90
88
89
87
91e
7
Py
8
KF
9
MgF2
CaF2
SrF2
BaF2
CaCl2
CaF2
10
11
12
13
14
a At 0.05 mmol scale in 0.5 mL solvent. b Isolated yield. c Enantiomeric
excesses were determined by HPLC methods. d Enantiomeric excess was 85%
when conducted at À20 °C with 57% yield after 48 h. e CaF2 (2 equiv) was
used and repeated at 0.1 mmol scale in 1.0 mL of solvent. (DHQ)2PHAL =
hydroquinine 1,4-phthalazinediyl diether, (DHQD)2PYR = hydroquini-
dine-2,5-diphenyl-4,6-pyrimidinediyl diether, (DHQ)2AQN = hydroqui-
nine anthraquinone-1,4-diyl diether, (DHQ)2PYR = hydroquinine 2,5-
diphenyl-4,6-pyrimidinediyl diether, (DHQD)2AQN = hydroquinidine
(anthraquinone-1,4-diyl) diether.
Table 4. Synthesis of Chiral MBH Alcoholsa
a At 0.05 mmol scale in 0.5 mL of DMAC. Enantiomeric excesses were determined by HPLC methods. Isolated yield. b At À10 °C, 5.0 equiv of H2O and
5.0 equiv of CaF2 were used. c At 0 °C, 2.0 equiv of H2O and 2.0 equiv of CaF2 were used. d At 0 °C, 5.0 equiv of H2O and 5.0 equiv of CaF2 were used.
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NOTE
Scheme 3. 18O-Labeling Experiments To Investigate the Reaction Mechanism
metabolites. Work is in progress to fully explore the substrate
scope and will be reported in due course.
(t, J = 7.8 Hz, 1H), 6.41 (s, 1H), 5.90 (s, 1H), 5.63 (d, J = 6.1 Hz, 1H),
3.74 (s, 3H), 3.34 (d, J = 6.1 Hz, 1H); 13C NMR (100 MHz, CDCl3,
ppm) δ 166.2, 148.1, 143.6, 140.9, 132.7, 129.2, 127.0, 122.6, 121.4,
72.2, 52.1; LRMS (ESI) m/z 236.1 (M À H+); HRMS (ESI) m/z
236.0565 (M À H+), calcd for C11H10O5N 236.0564.
’ EXPERIMENTAL SECTION
Methyl-3-hydroxy-2-methylene-3-(4-fluorophenyl) Propanoate (2d):
Colorless oil; 99% yield; 1H NMR (400 MHz, CDCl3, ppm) δ
7.36À7.32 (m, 2H), 7.04À7.00 (m, 2H), 6.33 (s, 1H), 5.83 (s, 1H),
5.54 (s, 1H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 166.7,
163.6, 161.1, 141.9, 137.1 (two peaks), 128.4, 128.3, 126.1, 115.4,
115.2, 72.6, 52.0; LRMS (ESI) m/z 209.0 (M À H+); HRMS (ESI) m/
z 209.0623 (M À H+), calcd for C11H10O3F 209.0619.
Typical Experimental Procedure for the Reaction be-
tween MBH Carbonate 1a and H2O Catalyzed by DABCO.
1a (29.2 mg, 0.1 mmol, 1.0 equiv) and H2O (4.0 μL, 0.2 mmol,
2.0 equiv) were dissolved in DMF (750 μL) and stirred at room
temperature for 2.0 min, followed by DABCO (1.12 mg, 0.01 mmol,
0.1 equiv). The reaction mixture was stirred at room temperature and
monitored by TLC. After an hour and complete consumption of 1a, the
reaction mixture was directly loaded onto a short silica gel column,
followed by gradient elution with petroleum ether/ethyl acetate mixture
(100/1À5/1 ratio). Removal of the solvent in vacuo affords product 2a
(18.1 mg) as pale yellow oil in 96% yield.
Typical Experimental Procedure for the Reaction between
MBH Carbonate 1a and H2O Catalyzed by (DHQD)2AQN. 1a
(29.2 mg, 0.1 mmol, 1.0 equiv), H2O (4.0 μL, 0.2 mmol, 2.0 equiv),
and CaF2 (15.6 mg, 0.2 mmol, 2.0 equiv) were dissolved in DMF
(1.5 mL) and stirred at 0 °C for 10.0 min, followed by
(DHQD)2AQN (8.58 mg, 0.01 mmol, 0.1 equiv). The reaction
mixture was stirred at 0 °C and monitored by TLC. After 72 h and
complete consumption of 1a, the reaction mixture was directly
loaded onto a short silica gel column, followed by gradient elution
with petroleum ether/ethyl acetate mixture (100/1À5/1 ratio).
Removal of the solvent in vacuo affords the product 5a (16.6 mg)
as pale yellow oil in 86% yield and 91% ee.
Methyl-3-hydroxy-2-methylene-3-(4-bromophenyl) Propanoate (2e):
Pale yellow oil; 99% yield; 1H NMR (400 MHz, CDCl3, ppm) δ 7.47 (d,
J = 9.6 Hz, 2H), 7.25 (d, J = 9.6 Hz, 2H), 6.34 (s, 1H), 5.82 (s, 1H), 5.51
(d, J = 5.4 Hz, 1H), 3.73 (s, 3H), 3.09 (d, J = 5.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3, ppm) δ 166.6, 141.5, 140.3, 131.6, 128.3, 126.5, 126.4,
121.8, 72.8, 52.1; LRMS (ESI) m/z 293.0 (M + Na+); HRMS (ESI) m/z
292.9770 (M + Na+), calcd for C11H11O3BrNa 292.9784.
Methyl-3-hydroxy-2-methylene-3-(2-chlorophenyl) Propanoate (2f):
1
Colorless oil; 94% yield; H NMR (400 MHz, CDCl3, ppm) δ 7.56
(dd, J = 7.6, 1.7 Hz, 1H), 7.36À7.22 (m, 3H), 6.33 (s, 1H), 5.98 (d, J =
4.7 Hz, 1H), 5.58 (s, 1H), 3.77 (s, 3H), 3.30 (d, J = 4.7 Hz, 1H); 13C
NMR (100 MHz, CDCl3, ppm) δ 166.7, 140.6, 138.3, 132.6, 129.2,
128.8, 128.0, 126.8, 126.7, 68.8, 51.9; LRMS (ESI) m/z 248.9 (M +
Na+); HRMS (ESI) m/z 249.0289 (M + Na+), calcd for C11H11O3Cl-
Na 249.0289.
Methyl-3-hydroxy-2-methylene-3-(4-methylphenyl) Propanoate (2g):
Colorless oil; 99% yield; 1H NMR (400 MHz, CDCl3, ppm) δ 7.25 (d,
J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 6.32 (s, 1H), 5.86 (s, 1H), 5.53
(d, J = 3.7 Hz, 1H), 3.71 (s, 3H), 3.04 (d, J = 3.7 Hz, 1H), 2.34 (s, 3H);
13C NMR (100 MHz, CDCl3, ppm) δ 166.7, 142.0, 138.3, 137.5, 129.1,
126.5, 125.8, 73.0, 51.9, 21.1; LRMS (EI) m/z 206.1 (M); HRMS (EI)
m/z 206.0946 (M), calcd for C12H14O3 206.0943.
Methyl-3-hydroxy-2-methylene-3-(2-naphthyl) Propanoate (2h):
White solid, mp 97.0À97.3 °C; 99% yield; 1H NMR (400 MHz, CDCl3,
ppm) δ 7.86À7.82 (m, 4H), 7.49À7.46 (m, 3H), 6.38 (s, 1H), 5.88 (s,
1H), 5.75 (d, J = 5.6 Hz, 1H), 3.73 (s, 3H), 3.14 (d, J = 5.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3, ppm) δ 166.8, 141.8, 138.5, 133.2, 133.0,
128.2, 128.1, 127.6, 126.4, 126.1, 126.0, 125.5, 124.5, 73.3, 52.0; LRMS
(ESI) m/z 265.0 (M + Na+); HRMS (ESI) m/z 265.0838 (M + Na+),
calcd for C15H14O3Na 265.0835.
Methyl-3-hydroxy-2-methylene-3-phenyl Propanoate (2a): Color-
less oil, 93% yield; 1H NMR (400 MHz, CDCl3, ppm) δ 7.40À7.26 (m,
5H), 6.34 (s, 1H), 5.83 (s, 1H), 5.57 (d, J = 5.7 Hz, 1H), 3.73 (s, 3H),
3.00 (d, J = 5.7 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ 166.7,
141.8, 141.2, 128.4, 127.8, 126.5, 126.1, 73.1, 51.9; LRMS (ESI) m/z
214.9 (M + Na+); HRMS (ESI) m/z 215.0684 (M + Na+), calcd for
C11H12O3Na 215.0679.
Methyl-3-hydroxy-2-methylene-3-(4-nitrophenyl) Propanoate (2b):
Colorless oil; 99% yield; 1H NMR (400 MHz, CDCl3, ppm) δ 8.19 (d,
J = 8.7 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 6.39 (s, 1H), 5.87 (s, 1H), 5.63
(d, J = 6.0 Hz, 1H), 3.74 (s, 3H), 3.33 (d, J = 6.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3, ppm) δ 166.3, 148.6, 147.3, 140.9, 127.3, 127.2,
123.5, 72.5, 52.1; LRMS (ESI) m/z 236.0 (M À H+); HRMS (ESI) m/
z 236.0560 (M À H+), calcd for C11H10O5N 236.0564.
Methyl-3-hydroxy-2-methylene-3-(3-nitrophenyl) Propanoate (2c):
Methyl-3-hydroxy-2-methylene-3-(4-methoxyphenyl) Propanoate
1
1
Colorless oil; 99% yield; H NMR (400 MHz, CDCl3, ppm) δ 8.25
(2i): Colorless oil; 82% yield; H NMR (400 MHz, CDCl3, ppm) δ
(t, J = 1.7 Hz, 1H), 8.15À8.13 (m, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.52
7.29À7.28 (d, J = 8.6 Hz, 2H), 6.87À6.85 (d, J = 8.6 Hz, 2H), 6.31 (s, 1H),
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NOTE
5.85 (t, J = 1.2 Hz, 1H), 5.52 (s,1H), 3.79 (s, 3H), 3.71 (s, 3H), 2.98 (br,
1H); 13C NMR (100 MHz, CDCl3, ppm) δ 166.8, 159.2, 142.1, 133.4,
127.8, 125.6, 113.8, 72.7, 55.2, 51.9; LRMS (ESI) m/z 244.9 (M + Na+);
HRMS (ESI) m/z 245.0794 (M + Na+), calcd for C12H14O4Na 245.0784.
Methyl-3-hydroxy-2-methylene-3-(3-thienyl) Propanoate (2j): Pale
yellow oil; 90% yield; 1H NMR (400 MHz, CDCl3, ppm) δ 7.27 (dd, J =
5.0, 2.9 Hz, 1H), 7.21 (d, J = 2.9 Hz, 1H), 7.02 (dd, J = 5.0, 1.0 Hz, 1H),
5.83 (s,1H), 5.61 (d, J = 5.9 Hz, 1H), 3.73 (s, 3H), 3.30À3.28 (m, 1H);
13C NMR (100 MHz, CDCl3, ppm) δ 166.7, 142.8, 141.5, 126.1, 126.0,
121.8, 69.8, 52.0; LRMS (ESI) m/z 220.9 (M + Na+); HRMS (ESI) m/z
221.0241 (M + Na+), calcd for C9H10O3SNa 221.0243.
(S)-(+)-Methyl-3-hydroxy-2-methylene-3-phenyl Propanoate (5a):
Pale yellow oil, 86% yield; 91% ee; [R]10D +76.4 (c 0.14, MeOH) {lit:
[R]22 +85.5 (c 1.11 MeOH), 84% ee, absolute configuration is
D
determined as S}.23 The ee was determined by HPLC analysis. LUX
Cellulose-2 (4.6 mm i.d. Â 250 mm); hexane/2-propanol = 90/10; flow
rate 1.0 mL/min; 25 °C; 210 nm; retention time = 9.7 min (major) and
15.8 min (minor).
(S)-(+)-Methyl-3-hydroxy-2-methylene-3-(4-fluorophenyl) Propanoate
(5b): Colorless oil; 80% yield; 81% ee; [R]21D +70.4 (c 0.50, MeOH).
The ee was determined by HPLC analysis. LUX Cellulose-2 (4.6 mm
i.d. Â 250 mm); hexane/2-propanol = 90/10; flow rate 1.0 mL/min;
25 °C; 230 nm; retention time = 8.3 min (major) and 10.6 min (minor).
(S)-(+)-Methyl-3-hydroxy-2-methylene-3-(4-
Methyl-3-hydroxy-2-methylene-3-(2-furyl) Propanoate (2k): Color-
1
less oil; 60% yield; H NMR (400 MHz, CDCl3, ppm) δ 7.34 (t, J =
0.8 Hz, 1H), 6.36 (s, 1H), 6.30 (dd, J = 3.2, 2.0 Hz, 1H), 6.23 (d, J =
3.2 Hz, 1H), 5.94 (s, 1H), 5.56 (s, 1H), 3.72 (s, 3H), 3.38 (br, 1H); 13C
NMR (100 MHz, CDCl3, ppm) δ 166.4, 154.1, 142.4, 139.4, 126.8,
110.4, 107.2, 67.4, 52.0; LRMS (ESI) m/z 204.6 (M + Na+); HRMS
(ESI) m/z 205.0474 (M + Na+), calcd for C9H10O4Na 205.0471.
tert-Butyl-3-hydroxy-2-methylene-3-phenyl Propanoate (2l): Col-
orless oil; 80% yield; 1H NMR (400 MHz, CDCl3, ppm) δ 7.38À7.27
(m, 5H), 6.25 (s, 1H), 5.72 (t, J = 1.2 Hz, 1H), 5.50 (s, 1H), 1.40 (s, 9H);
13C NMR (100 MHz, CDCl3, ppm) δ 165.7, 143.5, 141.7, 128.3, 127.7,
126.6, 125.1, 81.6, 73.4, 28.0; LRMS (ESI) m/z 256.9 (M + Na+); HRMS
(ESI) m/z 257.1150 (M + Na+), calcd for C14H18O3Na 257.1148.
3-Hydroxy-2-methylene-3-phenyl Propanenitrile (2m): Colorless
trifluoromethylphenyl) Propanoate (5c): Pale yellow oil; 88% yield;
91% ee; [R]22D +59.2 (c 0.25, MeOH); 1H NMR (400 MHz, CDCl3,
ppm) δ 7.63 (s, 1H), 7.53 (t, J = 6.3 Hz, 2H), 7.43 (t, J = 7.7 Hz, 1H),
6.35 (s, 1H), 5.84 (s, 1H), 5.57 (s, 1H), 3.70 (s, 3H), 3.57 (s, 1H); 13
C
NMR (100 MHz, CDCl3, ppm) δ 166.5, 142.3, 141.4, 130.8, 130.5,
130.0, 128.8, 126.6, 125.4, 124.6, 124.5 (two peaks), 123.4, 123.3 (three
peaks), 122.6, 72.5, 52.0; LRMS (ESI) m/z 258.9 (M À H+); HRMS
(ESI) m/z 259.0584 (M À H+), calcd for C12H10O3F3 259.0588. The ee
was determined by HPLC analysis. LUX Cellulose-2 (4.6 mm i.d. Â 250
mm); hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C;
230 nm; retention time = 5.6 min (major) and 6.7 min (minor).
(S)-(+)-Methyl-3-hydroxy-2-methylene-3-(3-chlorophenyl) Propano-
ate (5d): Colorless oil; 83% yield; 94% ee; [R]22D +57.1 (c 0.53, MeOH);
1H NMR (400 MHz, CDCl3, ppm) δ 7.34 (br, 1H), 7.25À7.21 (m, 3H),
6.32(s, 1H), 5.84(s,1H), 5.47 (s, 1H),3.69(s,3H);13C NMR (100 MHz,
CDCl3, ppm) δ 166.4, 143.3, 141.3, 134.2, 129.6, 127.8, 126.6, 126.5,
124.7, 72.4, 52.0; LRMS (EI) m/z 226.0 (M); HRMS (EI) m/z 226.0392
(M), calcd for C11H11O3Cl 226.0397. The ee was determined by HPLC
analysis. LUX Cellulose-2 (4.6 mm i.d. Â 250 mm); hexane/2-propanol =
90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention time = 7.8 min
(major) and 9.6 min (minor).
(S)-(+)-Methyl-3-hydroxy-2-methylene-3-(3-bromophenyl) Propano-
ate (5e): Colorless oil; 80% yield; 93% ee; [R]21D +46.7 (c 0.41, MeOH);
1H NMR (400 MHz, CDCl3, ppm) δ 7.53 (s, 1H), 7.42À7.40 (m, 1H),
7.30 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 6.36 (s, 1H), 5.84 (s, 1H),
5.51 (d, J = 5.4 Hz,1H), 3.73 (s, 3H), 3.19 (d, J = 5.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3, ppm) δ 166.5, 143.6, 141.3, 130.9, 129.9, 129.6, 126.7,
125.2, 122.5, 72.7, 52.1; LRMS (ESI) m/z 293.0 (M + Na+); HRMS (ESI)
m/z 292.9770 (M + Na+), calcd for C11H11O3BrNa 292.9784. The ee was
determined by HPLC analysis. LUX Cellulose-2 (4.6 mm i.d. Â 250 mm);
hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 230 nm;
retention time = 8.2 min (major) and 10.1 min (minor).
1
oil; 67% yield; H NMR (400 MHz, CDCl3, ppm) δ 7.42À7.36 (m,
5H), 6.10 (s, 1H), 6.02 (s, 1H), 5.28 (d, J = 2.2 Hz, 1H), 2.68À2.64 (m,
1H); 13C NMR (100 MHz, CDCl3, ppm) δ 139.0, 129.9, 128.5, 128.4,
126.3, 125.9, 116.8, 73.5; LRMS (ESI) m/z 158.1 (M À H+); HRMS
(ESI) m/z 158.0617 (M À H+), calcd for C10H8ON 158.0611.
P-[1-(Hydroxyphenyl)ethenyl]phosphonic Acid, Diethyl Ester (2n):
Yellow oil; 76% yield; 1H NMR (400 MHz, CDCl3, ppm) δ 7.40À7.28
(m, 5H), 6.08 (d, J = 21.9 Hz, 1H), 6.01 (dt, J = 45.7, 1.2 Hz, 1H), 5.48
(dd, J = 13.2, 5.2 Hz, 1H), 4.11À3.95 (m, 2H), 3.95À3.85 (m, 1H),
3.79À3.69 (m, 1H), 3.53 (d, J = 5.5 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H),
1.12 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 142.6,
140.9, 140.8, 129.8, 129.7, 128.2, 127.7, 126.7, 74.2, 74.0, 62.2, 62.1 (two
peaks), 62.0, 16.2, 16.1, 16.0, 15.9; 31P (161.9755 MHz, CDCl3, ppm) δ
17.4; LRMS (ESI) m/z 293.0 (M + Na+); HRMS (ESI) m/z 293.0925
(M + Na+), calcd for C13H19O4P 293.0913.
Methyl 3-Hydroxy-2-methylidenepentanoate (2o): Colorless oil;
60% yield; 1H NMR (400 MHz, CDCl3, ppm) δ 6.22 (s, 1H), 5.78 (s,
1H), 4.34À4.29 (m, 1H),3.76(s, 3H), 2.62 (d, J =6.6 Hz, 1H), 1.71À1.58
(m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ
167.0, 142.1, 125.1, 73.0, 51.8, 29.0, 10.0; LRMS (EI) m/z 144.1 (M+);
HRMS (EI) m/z 144.0784 (M+), calcd for C7H12O3 144.0786.
(S)-(+)-Methyl-3-hydroxy-2-methylene-3-(3,5-dichlorophenyl) Pro-
panoate (5f): Colorless oil; 85% yield; 89% ee; [R]22D +58.5 (c 0.35,
2-(Hydroxymethyl)-2-cyclopenten-1-one (4a): White solid, mp
1
1
55.0À56.7 °C; 50% yield; H NMR (400 MHz, CDCl3, ppm) δ 7.54
MeOH); H NMR (400 MHz, CDCl3, ppm) δ 7.28 (s, 3H), 6.40 (s,
1H), 5.89 (s, 1H), 5.48 (s, 1H), 3.76 (s, 3H); 13C NMR (100 MHz,
CDCl3, ppm) δ 166.3, 144.8, 140.7, 134.9, 127.8, 127.2, 125.0, 72.3,
52.2; LRMS (ESI) m/z 258.7 (M À H+); HRMS (ESI) m/z 258.9942
(M À H+), calcd for C11H9O3Cl2 258.9934. The ee was determined by
HPLC analysis. LUX Cellulose-2 (4.6 mm i.d. Â 250 mm); hexane/2-
propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 254 nm; retention
time = 5.9 min (major) and 6.7 min (minor).
- 7.52 (m, 1H), 4.39 - 4.38 (m, 2H), 2.67À2.63 (m, 2H), 2.47À2.45 (m,
2H); 13C NMR (100 MHz, CDCl3, ppm) δ 209.9, 159.0, 144.9, 57.5,
35.0, 26.8; LRMS (EI) m/z 112.1 (M+); HRMS (EI) m/z 112.0527
(M+), calcd for C6H8O2 112.0524.
2-(Hydroxyphenylmethyl)-2-cyclopenten-1-one (4b): Pale yellow
1
oil; 57% yield; H NMR (400 MHz, CDCl3, ppm) δ 7.36À7.23 (m,
6H), 5.50 (s, 1H), 3.85 (br, 1H), 2.54 (d, J = 1.6 Hz, 2H), 2.40À2.37 (m,
2H); 13C NMR (100 MHz, CDCl3, ppm) δ 209.5, 159.5, 147.7, 141.3,
128.3, 127.6, 126.2, 69.4, 35.1, 26.5; LRMS (ESI) m/z 211.0 (M + Na+);
HRMS (ESI) m/z 211.0726 (M + Na+), calcd for C12H12O2Na 211.0730.
2-(Hydroxymethyl)-2-cyclohexen-1-one (4c): Colorless oil; 61%
yield; 1H NMR (400 MHz, CDCl3, ppm) δ 7.02À6.91 (m, 1H),
4.20À4.18 (m, 2H), 2.40À2.32 (m, 4H), 1.99À1.92 (m, 2H); 13C
NMR (100 MHz, CDCl3, ppm) δ 200.7, 147.0, 138.2, 62.2, 38.2, 25.6,
22.7; LRMS (ESI) m/z 149.0 (M + Na+); HRMS (ESI) m/z 149.0566
(M + Na+), calcd for C7H10O2Na 149.0573.
(S)-(+)-Methyl-3-hydroxy-2-methylene-3-(3-thienyl) Propanoate (5g):
Pale yellow oil; 75% yield; 90% ee; [R]21D +31.1 (c 0.45, MeOH); HRMS
(ESI) m/z 221.0246 (M + Na+), calcd for C9H10O3SNa 221.0243. The
ee was determined by HPLC analysis. LUX Cellulose-2 (4.6 mm i.d. Â
250 mm); hexane/2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C;
230 nm; retention time = 10.1 min (major) and 14.6 min (minor).
(S)-(+)-Methyl-3-hydroxy-2-methylene-3-(3-nitrophenyl) Propano-
ate (5h): Colorless oil; 95% yield; 91% ee; [R]22D +55.6 (c 0.42, MeOH);
HRMS (EI) m/z 237.0647 (M+), calcd for C11H11O5N 237.0637. The ee
6898
dx.doi.org/10.1021/jo201096e |J. Org. Chem. 2011, 76, 6894–6900

The Journal of Organic Chemistry
NOTE
was determined by HPLC analysis. LUX Cellulose-2 (4.6 mm i.d. Â 250
mm); hexane/2-propanol = 90/10;flow rate 1.0 mL/min;25°C;230 nm;
retention time = 15.8 min (major) and 17.7 min (minor).
(4) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010,
110, 5447–5674.
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Kishi, Y. Org. Lett. 2002, 4, 4431–4434.
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349, 2407–2424.
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(S)-(+)-Methyl-3-hydroxy-2-methylene-3-(3-fluorophenyl) Propano-
ate (5i): Pale yellow oil; 90% yield; 91% ee; [R]21D +59.2 (c 0.5, MeOH);
1H NMR (400 MHz, CDCl3, ppm) δ 7.32À7.28 (m, 1H), 7.14À7.07
(m, 2H), 6.98À6.93 (m, 1H), 6.34 (s, 1H), 5.83 (s, 1H), 5.52 (s, 1H),
3.72 (s, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 166.6, 164.0, 161.6,
143.9, 143.8, 141.4, 129.9, 129.8, 126.6, 122.1 (two peaks), 114.7, 114.5,
113.6,113.3, 72.6 (two peaks), 52.0; LRMS (ESI) m/z 209.0 (M À H+);
HRMS (ESI) m/z 209.0623 (M À H+), calcd for C11H10O3F 209.0619.
The ee was determined by HPLC analysis. LUX Cellulose-2 (4.6 mm
i.d. Â 250 mm); hexane/2-propanol = 90/10; flow rate 1.0 mL/min;
25 °C; 210 nm; retention time = 7.5 min (major) and 9.4 min (minor).
(S)-(+)-Methyl-3-hydroxy-2-methylene-3-(3-methoxyphenyl) Pro-
13, 900–903.
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1995, 36, 3425–3428.
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hedron: Asymmetry 2003, 14, 43–45.
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ꢀ
(11) Ruano, J. L. G.; Fernꢀandez-Ibꢀa~nez, M. A.; Fernꢀandez-Salas,
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panoate (5j): Colorless oil; 83% yield; 93% ee; [R]21 +73.3 (c 0.12,
D
MeOH); 1H NMR (400 MHz, CDCl3, ppm) δ 7.16À7.12 (t, J = 8.2 Hz,
1H), 6.83À6.82 (t, J = 2.4 Hz, 2H), 6.72À6.70 (m, 1H), 6.22 (s,1H),
5.73 (s, 1H), 5.41À5.40 (d, J = 5.3 Hz, 1H), 3.68 (s, 3H), 3.60 (s, 3H),
3.16À3.14 (d, J = 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) δ
166.8, 159.7, 142.9, 141.7, 129.4, 126.3, 118.8, 113.3, 112.0, 73.2, 55.2,
52.0; LRMS (ESI) m/z 245.0 (M + Na+); HRMS (ESI) m/z 245.0785
(M + Na+), calcd for C12H14O4Na 245.0784. The ee was determined by
HPLC analysis. LUX Cellulose-2 (4.6 mm i.d. Â 250 mm); hexane/
2-propanol = 90/10; flow rate 1.0 mL/min; 25 °C; 230 nm; retention
time = 16.4 min (major) and 24.2 min (minor).
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8103–8106.
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7066–7069.
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Methyl-3-hydroxy18-2-methylene-3-phenyl Propanoate ([18O]-2a):
Colorless oil, 90% yield; LRMS (ESI) m/z 217.1 (M + Na+); HRMS
(ESI) m/z 217.0723 (M + Na+), calcd for C11H12O218ONa 217.0727.
The 18O incorporation of [18O]-2a was 83% as determined by MS
analysis (H218O is 90% atom of 18O).
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5a): Colorless oil, 85% yield. The 18O incorporation of [18O]-5a was
81% as determined by MS analysis (H218O is 90% atom of 18O).
1086–1092.
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’ ASSOCIATED CONTENT
S
Supporting Information. General information, HPLC
b
spectra of chiral products, and NMR spectra of the compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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2010, 46, 2856–2858.
(27) Sun, W.; Hong, L.; Liu, C.; Wang, R. Org. Lett. 2010, 12,
3914–3917.
’ AUTHOR INFORMATION
(28) Peng, J.; Cui, H.-L.; Chen., Y.-C. Sci. Chin. Ser. B 2011, 54,
81–86.
(29) Huang, J.-R.; Cui, H.-L.; Lei, J.; Sun, X.-H.; Chen, Y.-C. Chem.
Commun. 2011, 47, 4784–4786.
Corresponding Author
*E-mail: chmjzy@henu.edu.cn, chmtanch@nus.edu.sg.
(30) Deng, H.-P.; Wei, Y.; Shi, M. Eur. J. Org. Chem. 2011,
1956–1960.
’ ACKNOWLEDGMENT
(31) Yang, Y.-L.; Pei., C.-K.; Shi, M. Org. Biomol. Chem. 2011, 9,
3349–3358.
(32) Tan, B.; Candeias, N. R.; Barbas, C. F., III. J. Am. Chem. Soc.
2011, 133, 4672–4675.
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(34) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008,
Financial support from the National Natural Science Foundation
of China (21072044 to Z.J.), Excellent Youth Foundation of Henan
Scientific Committee (114100510003 to Z.J.), International Co-
operation Foundation of Henan Province (104300510062 to Z.J.
and C.-H.T.), and ARF Grants (R-143-000-337-112 and R-143-
000-342-112 to C.H.T.) is greatly appreciated.
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The Journal of Organic Chemistry
NOTE
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(43) In the presence of 10 mol % of (DHQD)2AQN at 0 °C, the
reaction between 1a and 2.0 equiv of H2O was conducted in DMF with
2.0 equiv of CaF2 as additive. The desired product 5a was achieved with
81% yield and 83% ee after 72 h.
(44) See the Supporting Information for details.
(45) The 18O incorporation of [18O]-2a was 83% as determined by
MS analysis (H218O is 90% atom of 18O).
(46) The 18O incorporation of [18O]-5a was 81% as determined by
MS analysis (H218O is 90% atom of 18O).
6900
dx.doi.org/10.1021/jo201096e |J. Org. Chem. 2011, 76, 6894–6900