Kinetic resolution of α-Methylene- β- Hydroxy esters catalyzed by Acyl transfer catalyst An -PIQ

Article abstract of DOI:10.1021/acs.joc.5b00073

A highly efficient nonenzymatic kinetic resolution of a series of structurally diverse racemic α-methylene-β-hydroxy esters utilizing the acyl transfer catalyst An-PIQ and propionic anhydride is reported. This procedure provides recovered alcohols with extremely high ee's (up to >99%) in reasonable conversions and excellent selectivity factors (S up to 108). Several synthetically important substrates were resolved in gram-scale reactions, and highly optically pure α-methylene-β-hydroxy esters were obtained with excellent S values and good yields.

Full text of DOI:10.1021/acs.joc.5b00073

Article
pubs.acs.org/joc
Kinetic Resolution of α‑Methylene-β-hydroxy Esters Catalyzed by
Acyl Transfer Catalyst An-PIQ
Shan-Shan Jiang, Qin-Chang Xu, Ming-Yu Zhu, Xingxin Yu,* and Wei-Ping Deng*
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong
Road, Shanghai 200237, P. R. China
S
* Supporting Information
ABSTRACT: A highly efficient nonenzymatic kinetic resolution of a series of structurally diverse racemic α-methylene-β-
hydroxy esters utilizing the acyl transfer catalyst An-PIQ and propionic anhydride is reported. This procedure provides recovered
alcohols with extremely high ee’s (up to >99%) in reasonable conversions and excellent selectivity factors (S up to 108). Several
synthetically important substrates were resolved in gram-scale reactions, and highly optically pure α-methylene-β-hydroxy esters
were obtained with excellent S values and good yields.
building blocks,8,9 which have been widely employed for the
synthesis of important optically pure natural products and
INTRODUCTION
■
Kinetic resolution (KR) via nucleophilic acyl transfer catalysis is
bioactive compounds (Figure 1). Therefore, much effort has
one of the most powerful and efficient strategies to obtain
optically pure compounds.1 Since the pioneering work of
been devoted to develop a highly efficient asymmetric MBH
Vedejs2a,b and Fu2c−e on the nonenzymatic KR of secondary
reaction for the preparation of optically pure or enantioen-
riched α-methylene-β-hydroxy esters.10,11 Notably, Hatakeya-
alcohols, using chiral phosphine and chiral 4-dimethylamino-
pyridine (DMAP) analogues as catalysts, respectively, asym-
ma11a developed a highly enantioselective MBH reaction of
metric nucleophilic acyl transfer catalysis for the KR of a variety
of secondary alcohols has been further developed.3 It is worth
noting that the amidine-based nucleophilic catalysts reported by
Birman,4 such as CF3-PIP,4a Cl-PIQ,4b BTM,4c and HBTM,4d,e
exhibited excellent tolerance to substrate scope, which can be
attributed to π−π and π−cation interactions between the sp2
functional groups of the substrates and acylated catalysts,
affording high selectivity factors. Through combination of the
key features of both Fu’s and Birman’s catalysts, a new variant
of nucleophilic catalyst has been designed, Fc-PIP,5a for the KR
of arylalkyl carbinols (S up to >1800) in our group. Although
much effort has been devoted to the development of
nonenzymatic catalysts for the KR of a variety of secondary
alcohols,4f,6 to the best of our knowledge, their application for
the KR of α-methylene-β-hydroxy esters (Morita−Baylis−
Hillman adducts, MBH adducts) by acylation has received
much less attention. In 2007 Connon7 reported the only
example of nonenzymatic acylative KR of MBH adducts
derived from aromatic aldehydes. However, very low selectivity
(S = 13) was obtained, probably due to the intrinsic flaw of two
planar sp2-hybridized substituents. More than that, a
nucleophilic nonenzymatic acylative KR of aliphatic aldehyde-
derived MBH adducts is unknown; thus, a great challenge still
remains.
aldehydes using β-isocupreidine (β-ICD) as the chiral amine
Figure 1. Natural products and important synthetic intermediates
obtained from optically pure MBH adducts.
MBH adducts are densely functionalized molecules (e.g.,
MBH-1 or MBH-2) and consequently are highly versatile chiral
Received: January 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00073
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
catalyst, and hexafluoroisopropyl acrylate (HFIPA) as the
activated alkene, and afforded the corresponding MBH adducts
in up to 99% ee. However, the efficient β-ICD−HFIPA
protocol still suffers from the formation of a large quantity of
dioxanone byproducts, especially when aliphatic aldehydes are
used as electrophiles.
ee and 83.1% ee, respectively, with a slightly higher selectivity
factor (S = 17) compared with Connon’s7 report. Encouraged
by this result, rac-1b was then chosen as the model substrate to
investigate the catalytic asymmetric KR capability of different
nucleophilic catalysts (Figure 2).4b,5 As shown in Table 1, it was
surprising that our newly developed catalyst An-PIQ gave the
optimal selectivity factor (S = 38) (Table 1, entry 2), whereas
other catalysts such as Cl-PIQ displayed lower S values (Table
1, entries 3−5). The selectivity factor S = 38 given by An-PIQ is
already the best result in the nonenzymatic KR of a MBH
adduct, and this exhibits potential practical utility for the
synthesis of optically pure MBH adducts, which prompted us to
further optimize the reaction system.
Screening solvents (Table 2, entries 1, 4−11) revealed that
diisopropyl ether (S = 56) gave, in general, an S value higher
than that of other solvents. Nevertheless, toluene and other
ethers (e.g., diethyl ether, methyl tert-butyl ether (MTBE), and
cyclopentyl methyl ether (CPME)) showed similar selectivities
(entries 4, 5, 6, 9) to those of diisopropyl ether. Our screening
of anhydrides revealed that propionic anhydride was optimal,
affording an excellent selectivity factor S = 89 (entries 12 vs 1,
13). An increase in the substrate concentration, to 0.4 M, was
found to be detrimental to the selectivity factor (entries 2 and
3). We then examined the effect of bases on the selectivity
factor of the KR and found that potasium carbonate gave the
optimal result, whereas Et3N, DIPEA (N,N-diisopropylethyl-
amine), and 2,6-lutidine were found to be slightly inferior to
potassium carbonate in terms of both stereoselectivities and
conversions (entries 15 vs 12, 14, 16).
Optimization of solvents, anhydrides, bases, and concen-
trations led us to establish that 5 mol % of An-PIQ/(EtCO)2O
(0.75 equiv)/K2CO3 (0.5 equiv)/iPr2O (0.1 M)/0 °C were the
optimal reaction conditions for catalytic KR of rac-1b. Under
these conditions, this protocol was investigated with different
MBH adducts as substrates, and the results are summarized in
Table 3. The KR of most benzhydryl esters 1b−i proceeded
smoothly, providing excellent selectivity factors (up to 108)
(Table 3, entries 1−8) and extremely high ee values (up to
99.9%) for unreacted alcohols at acceptable conversion ratios.
The bulkier alkyl groups (R1) gave lower selectivity factors and
reactivities (entries 6, 7). To better understand the role of the
benzhydryl group on the selectivity factor, we examined a
variety of substrates (1j−l) without the benzhydryl ester as R2
group. It was found that all these substrates gave dramatically
lower S values (entries 9−11) compared with 1i and 1b, which
indicated the crucial effect on stereoselective differentiation by
the benzhydryl group. Next, a series of structurally challenging
and synthetically versatile α- or β-functionalized MBH adducts
1m−p were also employed for this asymmetric KR (Table 3,
entries 12−15); if successful, this would afford optically pure
chiral building blocks for the synthesis of bioactive natural
products, such as tulipalin B, umbelactone, (+)-fostriecin,
We recently synthesized a highly efficient nucleophilic
catalyst An-PIQ5b for the KR of arylalkyl carbinols, with
excellent selectivity factors (up to 530). Considering the
current difficulties in the preparation of optically pure α-
methylene-β-hydroxy esters, we set out to design suitable
substrates and apply our developed catalysts in the KR of
racemic MBH adducts, derived from aliphatic aldehydes and
acrylates. However, several challenges are associated with this
procedure: (1) the choice of the suitable ester group, (2) the
relationship between individual π−π interaction of the alkene
and carbonyl group with the acylated catalyst, and (3) the role
of An-PIQ structure and whether it is decisive for the selectivity
factor. In order to address these issues and surmount the
difficulties in preparation of optically pure α-methylene-β-
hydroxy esters, a series of PIQ analogues and MBH adducts
were synthesized to test the feasibility.
Herein, we report a highly efficient nonenzymatic KR of
racemic α-methylene-β-hydroxy esters utilizing the acyl transfer
catalyst An-PIQ. This protocol provides recovered alcohols
with extremely high ee values (≥99%) and in reasonable
conversions and good-excellent selectivity factors (S up to 108).
RESULTS AND DISCUSSION
■
Initially, rac-1a was used as the substrate to test the feasibility of
the KR with Fc-PIP5a as the nucelophilic catalyst, which is a
useful catalyst for the KR of arylalkyl carbinols. The reaction
proceeded tediously when isobutyric anhydride was used as the
acylating agent in diisopropyl ether at room temperature for 12
h, providing unreacted (R)-alcohol (yield: 38%; ee: 84.2%),
(S)-acylated product 2a (yield: 44%; ee not determined), and
small quantities (15% yield) of byproduct 3 (Scheme 1). It is
obvious that benzyl ester 1a is not stable enough in the
presence of Fc-PIP.
Scheme 1. Fc-PIP-Catalyzed KR of α-Methylene-β-hydroxy
Esters 1a
In order to solve this problem, benzhydryl ester 1b was used
instead of 1a. To our delight, the reaction proceeded much
smoothly and provided unreacted 1b and acylated 2b in 43.7%
Figure 2. Nucleophilic catalysts.
B
DOI: 10.1021/acs.joc.5b00073
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 1. Screening of Catalysts in the KR of ( )-MBH Adduct 1b
b
c
d
entry
catalyst
t (h)
1b eeA (%)
2b eeE (%)
CHPLC (%)
S
1
2
3
4
5
Fc-PIP
An-PIQ
Np-PIQ
Br-PIQ
Cl-PIQ
6
43.7
65.1
66.3
46.2
54.7
83.1
90.2
81.8
73.2
58.9
34.5
41.9
44.8
38.7
48.2
17
38
20
10
7
5
4
18
18
a
b
c
Conditions: Substrate concentration 0.1 M, (iPrCO)2O 0.75 equiv, Et3N 0.75 equiv, catalyst 5 mol %. The ee value of the alcohol. The ee value of
d
the ester. The conversion is calculated from the ee values of the ester (S)-2b and unreacted alcohol (R)-1b.
a
Table 2. Screening of Solvents, Anhydrides Bases, and Concentrations
entry
1
solvent
(RCO)2O
base
Et3N
1 eeA (%)
eeE (%)
CHPLC (%)
S
iPr2O
iPr2O
iPr2O
Et2O
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Et
87.4
95.2
94.8
70.3
73.5
58.5
29.2
10.7
65.5
10.7
9.8
90.3
85.4
81.0
91.9
91.4
92.9
87.8
51.7
91.9
78.9
75.9
90.6
84.2
92.6
90.5
93.0
−88.3
49.2
52.7
53.9
43.3
44.6
38.6
25.0
17.2
41.6
11.9
11.4
51.9
48.8
49.9
52.1
49.5
49.4
56
47
35
50
49
49
20
3
b
2
Et3N
c
3
Et3N
4
Et3N
5
MTBE
CPME
THF
Et3N
6
Et3N
7
Et3N
8
CH3CN
toluene
CHCl3
DCM
iPr2O
iPr2O
iPr2O
iPr2O
iPr2O
iPr2O
Et3N
9
Et3N
47
9
10
11
12
13
14
15
16
Et3N
Et3N
8
Et3N
97.6
80.2
92.2
98.5
91.0
−86.3
89
29
86
97
88
45
Me
Et
Et3N
DIPEA
K2CO3
2,6-lutidine
K2CO3
Et
Et
d
17
Et
a
Conditions: Substrate concentration 0.1 M, 0.75 equiv of (iPrCO)2O, 0.75 equiv of Et3N, 5 mol % of An-PIQ. 0.2 mmol of substrate scale.
b
c
d
Substrate concentration 0.2 M. Substrate concentration 0.4 M. (R)-BTM4cas the catalyst.
(+)-phoslactomycin B, and DPD analogues (Figure 1).
Surprisingly, α-benzyloxy-substituted 1m gave an extremely
low selectivity factor (S = 3), probably due to a competitive
oxygen−cation interaction between the benzyloxy oxygen atom
and the carbonyl oxygen atom with the acylated An-PIQ.
According to Shinna’s reports,12 a carbonyl oxygen−cation
interaction was proposed to account for the high selectivity
factor in the KR of racemic 2-hydroxyalkanoates (Scheme 2). If
it is true, we envisaged that a sterically bulky protecting group
instead of benzyl would decrease or even avoid this
competition, which would therefore lead to a higher stereo-
selectivity. As expected, a TBS-protected substrate 1n was
found to be suitable for the KR, affording a dramatically
improved S value of 37. In order to further confirm the
existence of this hypothetical competitive oxygen−cation
interaction between the benzyloxy oxygen atom or the carbonyl
oxygen atom and the acylated An-PIQ, substrate 1o, with one
more carbon than 1m, was subjected to the KR and found to
give an improved S value equal to 24, providing corresponding
unreacted (R)-1o in 99.1% ee. To our delight, a TBS-protected
substrate 1p gave an excellent selectivity factor (S = 75), which
was comparable to that of substrates 1d−f with longer alkyl
chains.
In order to further demonstrate the utility of this protocol,
substrates 1b, 1n, 1p, 1o were chosen for scaled-up
investigations as shown in Scheme 3. The reactions proceeded
smoothly for all cases, to afford the unreacted alcohol (R)-1b,
(S)-1n, (R)-1p, (R)-1o in over 99.0% ee with good to excellent
selectivity factors (S = 20−82). (R)-1b and (R)-1o were then
subjected to transesterification to provide the corresponding
methyl esters (R)-6 and (R)-7 in 81% and 86% yield,
respectively, which can be used for the synthesis of some
C
DOI: 10.1021/acs.joc.5b00073
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 3. Scope and Generality of the An-PIQ-Catalyzed KR
b
d
d
entry
1
R1
R2
no.
1 eeA (%)
4 eeE (%)
CHPLC (%)
S
CAVG (%)
SAVG
Me
Et
CHPh2 (1b)
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
1
1
99.4
98.5
94.7
96.5
98.4
99.6
97.6
98.3
99.9
99.9
62.9
62.5
65.0
63.8
99.4
99.4
73.2
72.1
61.8
60.9
77.9
81.3
54.2
55.4
85.2
99.1
95.7
88.1
90.5
90.7
89.9
87.6
85.3
89.4
89.1
84.8
87.2
90.8
91.0
87.5
87.7
80.8
82.6
79.1
80.4
84.0
84.5
90.9
90.4
35.2
29.4
86.2
65.0
90.2
53.0
52.1
51.1
51.8
52.9
53.9
52.2
52.5
54.1
53.4
40.9
40.7
42.6
42.1
55.2
54.6
48.1
47.3
42.4
41.9
46.2
47.4
60.6
65.3
49.7
60.4
51.5
90
97
75
76
72
76
78
82
90
108
40
40
29
29
53
59
19
20
22
22
50
50
52.6
94
2
3
4
5
6
7
CHPh2 (1c)
CHPh2 (1d)
CHPh2 (1e)
CHPh2 (1f)
CHPh2 (1g)
CHPh2 (1h)
CHPh2 (1i)
51.5
53.4
52.4
53.8
40.8
42.4
54.9
47.7
42.2
46.8
63.0
76
74
80
99
40
29
56
20
22
50
3
nPr
nBu
iBu
iPr
cHex
c
8
PhCH2CH2
PhCH2CH2
Me
9
Me (1j)
10
11
12
CH2-1-naphthyl (1k)
CH2CH2Ph (1l)
CHPh2 (1m)
Me
BnOCH2
3.4
3.0
37
13
14
15
TBSOCH2
CHPh2 (1n)
CHPh2 (1o)
CHPh2 (1p)
37
24
75
BnOCH2CH2
TBSOCH2CH2
24
75
a
b
Conditions: 0.1 M substrate concentration, 0.75 equiv of (EtCO)2O, 0.5 equiv of K2CO3, 5 mol % of An-PIQ, 24 h. Calculated from the ee of the
c
d
ester and unreacted alcohol. 22 h. The average value of the two results.
Scheme 2. Proposed Transition State by Shinna12a
accordingly confirmed as R in comparison with the sign of
optical rotation from the literature report.11d Furthermore, the
simple transesterification of our synthetic 1i provided 1j, and
the sign of its optical rotation was found the same as that of 1j
derived from KR from Table 3 ([α]25 = +26.8°, c 0.01,
D
CHCl3), which established the absolute configuration of our
synthetic 1i as R. With the above three examples for
establishing the absolute configuration of our synthetic alcohols
as R configurations, the absolute configurations of the
remaining cases can be deduced accordingly by a similar
manner of steric control.
According to the results above, we speculated that
benzhydryl group has a major effect on the enantioselectivity
of the asymmetric KR, in collaboration with the carbonyl group
of the substrate. However, it is still not clear whether the
terminal double bond has a similar effect on enantioselectivity.
Therefore, a substrate without a carbon−carbon double bond
(1q) was prepared and used to investigate the role of the
double bond (Scheme 4). Notably, the selectivity factor (S =
24) of 1q dramatically decreased compared to that of the
substrate 1b (S = 97). This implies that the carbon−carbon
double bond plays an important role in π−π interaction
between the substrate and the acylated An-PIQ. Considering all
the above-mentioned parameters, a hypothetical transition state
was proposed, in which the high selectivity can be attributed to
π−cation interactions between the conjugated α,β-unsaturated
bioactive natural products as shown in Figure 1. For the KR of
1b and 1p, the catalyst An-PIQ was recovered in over 80% yield
and without loss in activity in the next KR process. The
absolute configurations of optically active 1b was determined
by comparing the optical rotation (our synthetic 6: [α]25
=
D
+17.4°, c 0.01, CHCl3, reported [α]25D = +10.2°, c 0.8, CHCl3)
and HPLC data for methyl ester 6 with that in the literature8d,13
and confirmed as R. Considering the structural diversity, the
optical rotation of our synthetic 1j was determined (72.1% ee,
[α]25 = +24.9°, c 0.01, CHCl3; reported 98% ee, [α]22
=
D
D
+28.1°, c 0.83, CHCl3), and its absolute configuration was
D
DOI: 10.1021/acs.joc.5b00073
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 3. Larger Scale Catalytic KR of Important Intermediates of Active Natural Products
Scheme 4. Investigation of the Substrate without a Carbon−Carbon Double Bond
ester and the acylated An-PIQ, as well as a π−π stacking
interaction between one phenyl ring of benzhydryl group and
the anthranyl group (Figure 3).
conversions and excellent selectivity factors (S up to 108). This
work complements the asymmetric MBH reaction, especially
for substrates derived from aliphatic aldehydes. This method
was also successfully applied to the KR on gram-scale of
important building blocks of several bioactive compounds, and
the corresponding optically pure α-methylene-β-hydroxy esters
were obtained with excellent ee values. In addition, this
protocol makes a breakthrough in the acylative KR of MBH
adducts containing the crucial benzhydryl ester. The high
selectivity is attributed to the combined interaction of double
CONCLUSION
■
In conclusion, we have developed a highly effective non-
enzymatic acylative KR of racemic α-methylene-β-hydroxy
esters with different alkyl side chains by use of the acyl transfer
catalyst An-PIQ and propionic anhydride, providing recovered
alcohols with extremely high ee’s (up to >99%) in reasonable
E
DOI: 10.1021/acs.joc.5b00073
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 3. Possible transition state for catalyst An-PIQ interacting with 1b.
bond, carbonyl group, and phenyl group of substrates with an
acyl ammonium intermediate. Further applications of the
products and mechanistic elucidation of the chirality induction
are ongoing in our laboratory.
EXPERIMENTAL SECTION
■
General Information. All reagents and starting materials were
obtained commercially and used as received unless otherwise stated.
Solvents and reagents were dried in advance. Catalyst An-PIQ, Np-
PIQ, Br-PIQ, Fc-PIP, (S)-Cl-PIQ, and (R)-BTM were synthesized
according to literature procedures.4b,5 1H NMR spectra were recorded
on a 400 MHz spectrometer in CDCl3. Chemical shifts are reported in
ppm with the internal TMS signal at 0.0 ppm as a standard. The
spectra are interpreted as s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br s = broad single, coupling constant(s) in
hertz, and relative integrations are reported. 13C NMR spectra were
recorded on a 400 MHz spectrometer in CDCl3. Chemical shifts are
reported in ppm with the internal chloroform signal at 77.0 ppm as a
standard.
added sodium borohydride (75.7 mg, 2 mmol). The reaction mixture
was stirred for 15 min at 0 °C, and then saturated aqueous ammonium
chloride was added. The mixture was extracted with DCM (3 × 30
mL), and the organic layer was washed with brine (20 mL) and dried
over sodium sulfate. After filtration and evaporation, the crude product
was purified by column chromatography (petroleum/EtOAc = 8/1) to
afford the product rac-1q.
Methods used for kinetic resolution experiments determination of
ee’s and calculation of conversions and selectivities were adopted from
previously published work.5 Enantiomeric excess values were
determined by analysis of HPLC traces, obtained by using chiralpak
AD-H, AS-H, OD-H, OJ-H, or IF-H columns with hexane and 2-
propanol or EtOAc as solvents. Selectivity factors and conversions
were calculated from the enantiomeric excess values of the ester
products and the recovered unreacted alcohol substrates according to
Kagan’s equations.14,15
1. Preparation of Racemic α-Methylene-β-hydroxy Esters 1
(Morita−Baylis−Hillmann reaction). To a rounded-bottomed flask
were added aldehyde (1.2 equiv), DABCO (0.3 equiv), and acrylate
ester (1.0 equiv) via syringe, and the resulting homogeneous solution
was stirred at room temperature and monitored by TLC. The mixture
was extracted with CH2Cl2 and water, and the combined organic
solution was washed with brine, dried over anhydrous Na2SO4, and
concentrated. The crude product was purified by column chromatog-
raphy on silica gel (petroleum/EtOAc = 6/1), to afford the product.
4. General Procedure for Nonenzymatic Resolution of Racemic
α-Methylene-β-hydroxy Esters 1 with An-PIQ. Under an atmosphere
of N2, catalyst An-PIQ (0.01 mmol), secondary alcohol (0.2 mmol),
K2CO3 (0.1 mmol), and isopropyl ether (2 mL) were sequentially
added to a 10 mL flame-dried Schlenk tube in an ice bath. After the
mixture was stirred at 0 °C for 5 min, propionyl anhydride (0.15
mmol) was added, the resulting solution was stirred at 0 °C for the
specified period and quenched by rapid addition of 0.2 mL of
methanol. The solution was warmed to room temperature and stirred
for an additional 2 h. The solvent was removed in vacuo and the
residue purified by silca gel chromatography (5−10% EtOAc/
petroleum) to separate the ester from the unreacted alcohol.
2. Preparation of Racemic Carboxylates of α-Methylene-β-
hydroxy Esters. To a solution of racemic α-methylene-β-hydroxy
ester (1.0 equiv) in i-Pr2O (0.2 M) were added ( )-tetramisole (0.5
equiv), K2CO3 (1.0 equiv), and (R3CO)2O (1.0 equiv). The mixture
was stirred at room temperature and monitored by TLC. The mixture
was extracted with DCM, and the combined organic phases were
washed with brine and concentrated by reduced pressure to get the
crude product, which was purified by column chromatography on silica
gel (petroleum/EtOAc = 10/1).
Benzyl (R)-3-Hydroxy-2-methylenebutanoate (1a).17 Colorless oil
(15.7 mg, 38% yield), 1H NMR (400 MHz, CDCl3): δ 7.44−7.29 (m,
5H), 6.27 (s, 1H), 5.85 (s, 1H), 5.23 (s, 2H), 4.74−4.59 (m, 1H), 2.68
(s, 1H), 1.39 (d, J = 6.3 Hz, 3H). The ee was determined by HPLC
(Chiralcel IF, 1 mL/min, 90/10 hexane/i-PrOH, λ = 254 nm,
retention time: (R) 7.55 min, (S) 8.49 min.
Benzhydryl (R)-3-Hydroxy-2-methylenebutanoate (1b). Colorless
1
oil (26.5 mg, 47% yield), H NMR (400 MHz, CDCl3): δ 7.47−7.26
3. Preparation of Benzhydryl 3-Hydroxybutanoate (rac-1q).
Compound 8 was prepared according to literature procedures.16 To
a solution of 8 (536.6 mg, 2 mmol) in ethanol (8 mL) at 0 °C was
(m, 10H), 6.96 (s, 1H), 6.39 (s, 1H), 5.90 (s, 1H), 4.71−4.62 (m,
1H), 2.60 (d, J = 5.5 Hz, 1H), 1.39 (d, J = 6.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 165.6, 143.9, 140.0, 128.6, 128.1, 127.0(6),
F
DOI: 10.1021/acs.joc.5b00073
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
127.0(5), 124.4, 77.5, 67.0, 22.2; HRMS (EI-TOF): Calcd for [M]+
Benzhydryl (R)-3-Hydroxy-2-methylene-5-phenylpentanoate (1i).
Colorless oil (33.5 mg, 45% yield), H NMR (400 MHz, CDCl3): δ
C18H18O3: 282.1256, found: 282.1255. (R)-1b: [α]25 = +14.6° (c
1
D
0.01, CHCl3) (99.1% ee). The ee was determined by HPLC (Chiralcel
OJ, 1 mL/min, 80/20 hexane/i-PrOH, λ = 254 nm, retention time:
(R) 18.78 min, (S) 23.69 min.
7.36−7.14 (m, 15H), 6.95 (s, 1H), 6.41 (s, 1H), 5.89 (s, 1H), 4.52−
4.43 (m, 1H), 2.85−2.57 (m, 2H), 2.54 (d, J = 6.3 Hz, 1H), 2.01−1.86
(m, 2H); 13C NMR (100 MHz, CDCl3): δ 165.5, 142.8, 141.6, 140.0,
139.9, 128.6, 128.5, 128.4, 128.0(8), 128.0(6), 127.1, 127.0, 125.9,
125.5, 77.5, 70.9, 37.8, 32.1; HRMS (ESI-TOF): Calcd for [M + Na]+
Benzhydryl (R)-3-Hydroxy-2-methylenepentanoate (1c). Color-
1
less oil (28.4 mg, 48% yield), H NMR (400 MHz, CDCl3): δ 7.39−
C25H24O3Na: 395.1623, found: 395.1622. (R)-1i: [α]25 = +17.6° (c
7.26 (m, 10H), 6.94 (s, 1H), 6.41 (s, 1H), 5.88 (s, 1H), 4.38 (m, 1H),
2.49 (d, J = 6.6 Hz, 1H), 1.79−1.56 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 164.5, 141.6, 139.0, 138.9(8), 127.6,
127.0, 126.0(1), 126.0(0), 124.3, 76.4, 71.9, 28.2, 9.0; HRMS (EI-
TOF): Calcd for [M]+ C19H20O3: 296.1412, found: 296.1413. (R)-1c:
[α]25D = +11.9° (c 0.01, CHCl3) (96.5% ee). The ee was determined
by HPLC (Chiralcel AS, 1 mL/min, 40/1 hexane/i-PrOH, λ = 254
nm, retention time: (S) 16.89 min, (R) 19.82 min.
D
0.01, CHCl3) (99.4% ee). The ee was determined by HPLC (Chiralcel
OJ, 1 mL/min, 80/20 hexane/i-PrOH, λ = 254 nm, retention time: (S)
23.74 min; (R) 30.76 min.
Methyl (R)-3-Hydroxy-2-methylene-5-phenylpentanoate (1j).
1
Colorless oil (22.9 mg, 52% yield), H NMR (400 MHz, CDCl3): δ
7.31−7.15 (m, 5H), 6.24 (s, 1H), 5.81 (s, 1H), 4.46−4.38 (m, 1H),
3.78 (s, 3H), 2.89−2.68 (m, 2H), 2.64 (d, J = 6.7 Hz, 1H), 2.03−1.94
(m, 2H); 13C NMR (100 MHz, CDCl3): δ 165.6, 143.3, 140.0, 139.9,
128.6, 128.1, 127.1, 127.0, 125.1, 77.4, 69.9, 45.5, 24.8, 23.3, 21.8;
HRMS (EI-TOF): Calcd for [M]+ C13H16O3: 220.1099, found:
220.1101. (R)-1j: [α]25D = +24.9° (c 0.01, CHCl3) (72.1% ee). The ee
was determined by HPLC (Chiralcel AS, 1 mL/min, 90/10 hexane/i-
PrOH, λ = 254 nm, retention time: (R) 6.76 min, (S) 8.08 min.
Naphthalen-1-ylmethyl (R)-3-Hydroxy-2-methylenebutanoate
(1k). Colorless oil (29.2 mg, 57% yield). 1H NMR (400 MHz,
CDCl3): δ 8.02 (d, J = 8.2 Hz, 1H), 7.93−7.84 (m, 2H), 7.60−7.42
(m, 4H), 6.23 (s, 1H), 5.82 (s, 1H), 5.68 (s, 2H), 4.68−4.59 (m, 1H),
2.63 (d, J = 5.6 Hz, 1H), 1.38 (d, J = 6.5 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 166.5, 143.6, 133.8, 131.7, 131.2, 129.5, 128.8, 127.5,
126.7, 126.0, 125.3, 124.5, 123.4, 67.0, 65.0, 22.2; HRMS (EI-TOF):
Benzhydryl (R)-3-Hydroxy-2-methylenehexanoate (1d). Colorless
1
oil (28.5 mg, 46% yield), H NMR (400 MHz, CDCl3): δ 7.45−7.27
(m, 10H), 6.95 (s, 1H), 6.39 (s, 1H), 5.87 (s, 1H), 4.53−4.38 (m,
1H), 2.48 (d, J = 5.7 Hz, 1H), 1.70−1.54 (m, 2H), 1.53−1.27 (m,
2H), 0.91 (t, J = 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3): δ 165.6,
143.0, 140.0, 139. 9(9), 128.6, 128.0, 127.1, 127.0, 125.1, 77.4, 71.4,
38.5, 19.0, 13.8; HRMS (EI-TOF): Calcd for [M]+ C20H22O3:
310.1569, found: 310.1571. (R)-1d: [α]25 = +13.9° (c 0.01, CHCl3)
D
(99.6% ee). The ee was determined by HPLC (Chiralcel AS, 1 mL/
min, 40/1 hexane/i-PrOH, λ = 254 nm, retention time: (S) 14.36 min,
(R) 16.92 min.
Benzhydryl (R)-3-Hydroxy-2-methyleneheptanoate (1e). White
solid (30.5 mg, 47% yield), mp 42−43 °C. 1H NMR (400 MHz,
CDCl3): δ 7.41−7.27 (m, 10H), 6.95 (s, 1H), 6.39 (s, 1H), 5.88 (s,
1H), 4.49−4.40 (m, 1H), 2.47 (d, J = 6.6 Hz, 1H), 1.74−1.60 (m,
2H), 1.48−1.21 (m, 4H), 0.87 (t, J = 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 165.6, 143.0, 140.0, 139.9(8), 128.6, 128.0, 127.1,
127.0, 125.1, 77.4, 71.7, 36.0, 28.0, 22.5, 14.0; HRMS (EI-TOF):
Calcd for [M]+ C16H16O3: 256.1099, found: 256.1100. (R)-1k: [α]25
D
= +7.8° (c 0.01, CHCl3) (61.8% ee). The ee was determined by HPLC
(Chiralcel OD, 1 mL/min, 90/10 hexane/i-PrOH, λ = 254 nm,
retention time: (R) 10.11 min, (S) 11.24 min.
Phenethyl (R)-3-Hydroxy-2-methylenebutanoate (1l). Colorless
1
Calcd for [M]+ C21H24O3: 324.1725, found: 324.1724. (R)-1e: [α]25
oil (23.3 mg, 53% yield). H NMR (400 MHz, CDCl3): δ 7.43−7.13
D
= +13.7° (c 0.01, CHCl3) (98.3% ee). The ee was determined by
HPLC (Chiralcel AS, 1 mL/min, 40/1 hexane/i-PrOH, λ = 254 nm,
retention time: (S) 13.60 min, (R) 15.99 min.
(m, 5H), 6.19 (s, 1H), 5.80 (s, 1H), 4.45−4.36 (m, 1H), 4.40 (t, J =
6.6 Hz, 2H), 3.00 (t, J = 6.6 Hz, 2H), 2.57 (s, 1H), 1.35 (d, J = 6.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 166.5, 143.7, 137.7, 128.8,
128.6, 126.7, 124.1, 67.0, 65.3, 35.1, 22.1; HRMS (EI-TOF): Calcd for
[M]+ C13H16O3: 220.1099, found: 220.1106. (R)-1l: [α]25D = +9.9° (c
0.01, CHCl3) (81.3% ee). The ee was determined by HPLC (Chiralcel
IF, 1 mL/min, 90/10 hexane/i-PrOH, λ = 254 nm, retention time: (R)
7.58 min, (S) 11.70 min.
Benzhydryl (R)-3-Hydroxy-5-methyl-2-methylenehexanoate (1f).
White solid (29.8 mg, 46% yield), mp 50−51 °C. 1H NMR (400 MHz,
CDCl3): δ 7.44−7.17 (m, 10H), 6.95 (s, 1H), 6.38 (s, 1H), 5.89 (s,
1H), 4.59−4.46 (m, 1H), 2.48 (s, 1H), 1.86−1.71 (m, 1H), 1.61−1.49
(m, 1H), 1.49−1.35 (m, 1H), 0.91 (d, J = 6.1 Hz, 6H); 13C NMR (100
MHz, CDCl3): δ 165.6, 143.3, 140.0, 139.9, 128.6, 128.1, 127.1, 127.0,
125.1, 77.4, 69.9, 45.5, 24.8, 23.3, 21.8; HRMS (EI-TOF): Calcd for
Benzhydryl (S)-4-(Benzyloxy)-3-hydroxy-2-methylenebutanoate
(1m). Colorless oil (28.7 mg, 37% yield). 1H NMR (400 MHz,
CDCl3) δ 7.36−7.26 (m, 15H), 6.93 (s, 1H), 6.52 (s, 1H), 6.09 (s,
1H), 4.84−4.76 (m, 1H), 4.53 (s, 2H), 3.72 (dd, J = 9.6, 3.4 Hz, 1H),
3.40 (dd, J = 9.6, 7.6 Hz, 1H), 2.90 (d, J = 4.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 163.9, 139.0, 138.9, 138.3, 136.8, 127.5(6),
127.5(5), 127.5, 127.0, 126.9(8), 126.8, 126.7, 126.0(9), 126.0(7),
126.0, 76.4, 72.6, 72.3, 68.5; HRMS (ESI-TOF): Calcd for [M + Na]+
[M]+ C21H24O3: 324.1725, found: 324.1726. (R)-1f: [α]25 = +22.0°
D
(c 0.01, CHCl3) (99.9% ee). The ee was determined by HPLC
(Chiralcel AD, 1 mL/min, 100/5 hexane/i-PrOH, λ = 254 nm,
retention time: (R) 16.75 min, (S) 19.62 min.
Benzhydryl (R)-3-Hydroxy-4-methyl-2-methylenepentanoate
(1g). Colorless oil (36.6 mg, 59% yield), 1H NMR (400 MHz,
CDCl3): δ 7.44−7.26 (m, 10H), 6.93 (s, 1H), 6.43 (s, 1H), 5.84 (s,
1H), 4.17−4.09 (m, 1H), 2.45 (d, J = 7.6 Hz, 1H), 1.96−1.85 (m,
1H), 0.93 (d, J = 6.7 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 165.7, 141.8, 140.1, 140.0, 128.6, 128.0,
127.0(2), 127.0(1), 126.2, 77.5, 77.4, 32.7, 19.6, 17.4; HRMS (EI-
TOF): Calcd for [M]+ C20H22O3: 310.1569, found: 310.1568. (R)-1g:
[α]25D = +7.1° (c 0.01, CHCl3) (62.9% ee). The ee was determined by
HPLC (Chiralcel AD, 1 mL/min, 100/5 hexane/i-PrOH, λ = 254 nm,
retention time: (R) 18.17 min, (S) 20.51 min.
C25H24O4Na: 411.1572, found: 411.1570. (S)-1m: [α]25 = +9.1° (c
D
0.01, CHCl3) (55.4% ee). The ee was determined by HPLC (Chiralcel
AS, 1 mL/min, 60/1 hexane/i-PrOH, λ = 254 nm, retention time: (R)
28.68 min, (S) 32.58 min.
Benzhydryl (S)-4-((tert-Butyldimethylsilyl)oxy)-3-hydroxy-2-meth-
1
ylenebutanoate (1n). Colorless oil (41.2 mg, 50% yield). H NMR
(400 MHz, CDCl3): δ 7.41−7.25 (m, 10H), 6.96 (s, 1H), 6.52 (s, 1H),
6.07 (s, 1H), 4.65−4.59 (m, 1H), 3.86 (dd, J = 10.0, 3.8 Hz, 1H), 3.46
(dd, J = 10.0, 6.5 Hz, 1H), 2.98 (d, J = 4.9 Hz, 1H), 0.87 (s, 9H), 0.01
(s, 3H), 0.00 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.9, 140.1,
140.0, 139.5, 128.6, 128.5, 128.0, 127.9(6), 127.2, 127.0, 126.9, 77.3,
70.8, 66.4, 25.9, 18.3, −5.4(0), −5.4(3); HRMS (ESI-TOF): Calcd for
Benzhydryl (R)-2-(Cyclohexyl(hydroxy)methyl)acrylate (1h).
1
White solid (39.9 mg, 57% yield), mp 87−89 °C. H NMR (400
MHz, CDCl3): δ 7.42−7.27 (m, 10H), 6.93 (s, 1H), 6.40 (s, 1H), 5.80
(s, 1H), 4.16−4.08 (m, 1H), 2.43 (d, J = 7.8 Hz, 1H), 1.96−1.86 (m,
1H), 1.73−1.50 (m, 5H), 1.23−0.83 (m, 5H); 13C NMR (100 MHz,
CDCl3): δ 165.7, 141.6, 140.0, 139.9(6), 128.6, 128.0, 127.0, 126.2,
77.4, 77.1, 42.5, 30.0, 28.1, 26.4, 26.1, 25.9; HRMS (EI-TOF): Calcd
[M + Na]+ C24H32O4NaSi: 435.1968, found: 435.1968. (S)-1n: [α]25
D
= +19.4° (c 0.01, CHCl3) (98.3% ee). The ee was determined by
HPLC (Chiralcel OD, 1 mL/min, 40/1 hexane/i-PrOH, λ = 254 nm,
retention time: (S) 6.08 min, (R) 7.65 min.
Benzhydryl (R)-5-(Benzyloxy)-3-hydroxy-2-methylenepentanoate
(1o). Colorless oil (31.4 mg, 39% yield). 1H NMR (400 MHz,
CDCl3): δ 7.55−7.18 (m, 15H), 6.93 (s, 1H), 6.45 (s, 1H), 6.05−6.00
(m, 1H), 4.84−4.68 (m, 1H), 4.51 (s, 2H), 3.77−3.61 (m, 2H), 3.60
for [M]+ C23H26O3: 350.1882, found: 350.1884. (R)-1h: [α]25
=
D
+5.7° (c 0.01, CHCl3) (61.4% ee). The ee was determined by HPLC
(Chiralcel OJ, 1 mL/min, 80/20 hexane/i-PrOH, λ = 254 nm,
retention time: (S) 10.02 min, (R) 14.33 min.
G
DOI: 10.1021/acs.joc.5b00073
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(d, J = 4.8 Hz, 1H), 2.13−1.96 (m, 1H), 1.96−1.74 (m, 1H); 13C
NMR (100 MHz, CDCl3): δ 165.3, 142.5, 140.1, 137.9, 128.6, 128.5,
128.0, 127.9(8), 127.8, 127.7(6), 127.1, 127.0, 125.5, 77.3, 73.4, 70.2,
68.6, 35.8; HRMS (ESI-TOF): Calcd for [M + Na]+ C26H26O4Na:
Benzhydryl (S)-2-Methylene-3-(propionyloxy)pentanoate (4c).
Colorless oil (35.2 mg, 50% yield). H NMR (400 MHz, CDCl3): δ
1
7.39−7.27 (m, 10H), 6.95 (s, 1H), 6.42 (s, 1H), 5.81 (s, 1H), 5.70−
5.62 (m, 1H), 2.40−2.27 (m, 2H), 1.89−1.76 (m, 1H), 1.76−1.63 (m,
1H), 1.13 (t, J = 7.5 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 172.3, 163.4, 139.1, 139.0(3), 139.0(1), 127.5, 127.0,
126.9, 126.1, 126.0, 124.8, 76.5, 71.6, 26.7, 26.1, 8.5, 8.1; HRMS (EI-
TOF): Calcd for [M]+ C22H24O4: 352.1675, found: 352.1680. (S)-4c:
425.1729, found: 425.1729. (R)-1o: [α]25 = +18.6° (c 0.01, CHCl3)
D
(99.8% ee). The ee was determined by HPLC (Chiralcel AS, 1 mL/
min, 100/5 hexane/i-PrOH, λ = 254 nm, retention time: (S) 13.37
min; (R) 15.04 min.
[α]25 = −14.8° (c 0.01, CHCl3) (89.9% ee). The ee was determined
Benzhydryl (R)-5-((tert-Butyldimethylsilyl)oxy)-3-hydroxy-2-
D
1
methylenepentanoate (1p). Colorless oil (40.9 mg, 48% yield). H
by HPLC (Chiralcel AD, 1 mL/min, 40/1 hexane/i-PrOH, λ = 254
nm, retention time: (S) 15.68 min, (R) 20.30 min.
NMR (400 MHz, CDCl3): δ 7.44−7.27 (m, 10H), 6.93 (s, 1H), 6.47
(s, 1H), 6.10−6.02 (m, 1H), 4.84−4.68 (m, 1H), 4.01 (d, J = 4.1 Hz,
1H), 3.94−3.73 (m, 2H), 2.01−1.86 (m, 1H), 1.78−1.64 (m, 1H),
0.90 (s, 9H), 0.08 (s, 3H), 0.07(5) (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 165.2, 142.6, 140.2, 128.5(6), 128.5(5), 128.0, 127.9, 127.1,
127.0, 125.3, 77.2, 70.6, 62.2, 37.7, 25.9, 18.1, −5.5, −5.6; HRMS
(ESI-TOF): Calcd for [M + Na]+ C25H34O4NaSi: 449.2124, found:
Benzhydryl (S)-2-Methylene-3-(propionyloxy)hexanoate (4d).
1
Colorless oil (38.1 mg, 52% yield). H NMR (400 MHz, CDCl3): δ
7.51−7.27 (m, 10H), 6.96 (s, 1H), 6.40 (s, 1H), 5.81 (s, 1H), 5.78−
5.66 (m, 1H), 2.39−2.23 (m, 2H), 1.78−1.62 (m, 2H), 1.45−1.28 (m,
2H), 1.13 (t, J = 7.5 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 172.3, 163.4, 139.5, 139.0(2), 139.0(0), 127.5, 127.0,
126.9, 126.2, 126.0, 124.5, 76.5, 70.5, 35.4, 26.7, 17.7, 12.7, 8.1; HRMS
(EI-TOF): Calcd for [M]+ C23H26O4: 366.1831, found: 366.1833. (S)-
449.2122. (R)-1p: [α]25 = +20.9° (c 0.01, CHCl3) (99.7% ee). The
D
ee was determined by HPLC (Chiralcel AD, 1 mL/min, 40/1 hexane/
i-PrOH, λ = 254 nm, retention time: (S) 11.58 min, (R) 12.64 min.
Benzhydryl (R)-3-Hydroxybutanoate (1q). White solid (29.2 mg,
54% yield), mp 45−46 °C. 1H NMR (400 MHz, CDCl3): δ 7.42−7.26
(m, 10H), 6.91 (s, 1H), 4.27−4.16 (m, 1H), 2.87 (d, J = 3.7 Hz, 1H),
2.62 (dd, J = 16.5, 3.7 Hz, 1H), 2.55 (dd, J = 16.5, 8.5 Hz, 1H), 1.22
(d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 171.8, 140.0,
139.9, 128.5(9), 128.5(8), 128.1, 128.0, 127.2, 127.1, 77.3, 64.3, 43.2,
22.5; HRMS (EI-TOF): Calcd for [M]+ C17H18O3: 270.1256, found:
4d: [α]25 = −14.2° (c 0.01, CHCl3) (85.3% ee). The ee was
D
determined by HPLC (Chiralcel AD, 1 mL/min, 60/1 hexane/i-
PrOH, λ = 254 nm, retention time: (S) 17.60 min, (R) 19.54 min.
Benzhydryl (S)-2-Methylene-3-(propionyloxy)heptanoate (4e).
1
Colorless oil (38.0 mg, 50% yield). H NMR (400 MHz, CDCl3): δ
7.44−7.26 (m, 10H), 6.96 (s, 1H), 6.39 (s, 1H), 5.80 (s, 1H), 5.70
(dd, J = 7.7, 4.7 Hz, 1H), 2.43−2.22 (m, 2H), 1.82−1.61 (m, 2H),
1.30−1.23 (m, 4H), 1.13 (t, J = 7.6 Hz, 3H), 0.84 (t, J = 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 172.3, 163.4, 139.5, 139.0, 138.9(9),
127.5, 127.0, 126.9, 126.2, 126.0, 124.6, 76.5, 70.8, 33.0, 26.7, 26.5,
21.3, 12.9, 8.1; HRMS (EI-TOF): Calcd for [M]+ C24H28O4:
270.1258. (R)-1q: [α]25 = −15.5° (c 0.01, CHCl3) (70.7% ee). The
D
ee was determined by HPLC (Chiralcel AS, 1 mL/min, 90/10 hexane/
i-PrOH, λ = 254 nm, retention time: (S) 9.68 min, (R) 17.48 min.
Benzyl (S)-3-(Isobutyryloxy)-2-methylenebutanoate (2a). Color-
380.1988, found: 380.1989. (S)-4e: [α]25 = −12.1° (c 0.01,
D
1
less oil (24.3 mg, 44% yield). H NMR (400 MHz, CDCl3): δ 7.44−
CHCl3) (89.1% ee). The ee was determined by HPLC (Chiralcel
AS, 1 mL/min, 99.5/0.5 hexane/i-PrOH, λ = 254 nm, retention time:
(S) 4.87 min, (R) 8.10 min.
7.30 (m, 5H), 6.35 (s, 1H), 5.86 (s, 1H), 5.75 (q, J = 6.5 Hz, 1H),
5.31−5.16 (m, 2H), 2.61−2.51 (m, 1H), 1.42 (d, J = 6.5 Hz, 3H), 1.17
(dd, J = 6.8, 5.3 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 174.7,
164.1, 140.3, 134.7, 127.6, 127.2, 127.1, 123.8, 66.8, 65.6, 33.0, 19.1,
17.9, 17.8; HRMS (EI-TOF): Calcd for [M]+ C16H20O4: 276.1362,
found: 276.1368.
Benzhydryl (S)-5-Methyl-2-methylene-3-(propionyloxy)-
1
hexanoate (4f). Colorless oil (38.8 mg, 51% yield). H NMR (400
MHz, CDCl3): δ 7.46−7.26 (m, 10H), 6.96 (s, 1H), 6.38 (s, 1H),
5.85−5.72 (m, 2H), 2.44−2.23 (m, 2H), 1.65−1.51 (m, 3H), 1.13 (t, J
= 7.6 Hz, 3H), 0.93−0.81 (m, 6H); 13C NMR (100 MHz, CDCl3): δ
172.3, 163.3, 140.0, 138.9(8), 138.9(7), 127.5, 127.0, 126.9, 126.2,
125.9, 124.4, 76.5, 69.4, 42.6, 26.7, 23.9, 22.1, 20.7, 8.1; HRMS (EI-
TOF): Calcd for [M]+ C24H28O4: 380.1988, found: 380.1989. (S)-4f:
Benzhydryl (S)-3-(Isobutyryloxy)-2-methylenebutanoate (2b).
1
White solid (35.2 mg, 50% yield), mp 53−54 °C. H NMR (400
MHz, CDCl3): δ 7.41−7.22 (m, 10H), 6.96 (s, 1H), 6.41 (s, 1H), 5.87
(s, 1H), 5.83−5.74 (m, 1H), 2.56−2.45 (m, 1H), 1.40 (d, J = 6.2 Hz,
3H), 1.19−1.05 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 174.7,
163.3, 140.3, 139.0, 127.5, 127.0, 126.9, 126.1, 126.0, 124.2, 76.5, 66.9,
33.0, 19.0, 17.8; HRMS (EI-TOF): Calcd for [M]+ C22H24O4:
[α]25 = −23.6° (c 0.01, CHCl3) (84.2% ee). The ee was determined
D
by HPLC (Chiralcel AS, 0.8 mL/min, 60/1 hexane/i-PrOH, λ = 254
nm, retention time: (S) 5.10 min, (R) 6.37 min.
352.1675, found: 352.1676. (S)-2b: [α]25 = −15.1° (c 0.01, CHCl3)
Benzhydryl (S)-4-Methyl-2-methylene-3-(propionyloxy)-
pentanoate (4g). Colorless oil (29.3 mg, 40% yield). 1H NMR
(400 MHz, CDCl3): δ 7.50−7.27 (m, 10H), 6.94 (s, 1H), 6.43 (d, J =
0.9 Hz, 1H), 5.76 (t, J = 1.0 Hz, 1H), 5.54 (dd, J = 5.6, 0.7 Hz, 1H),
2.44−2.28 (m, 2H), 2.14−2.01 (m, 1H), 1.14 (t, J = 7.6 Hz, 3H),
0.90−0.84 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 172.3, 163.4,
139.1, 139.0, 138.6, 127.5, 127.0, 126.9, 126.2, 125.9, 125.4, 76.5, 75.1,
30.3, 26.7, 18.0, 16.0, 8.1; HRMS (EI-TOF): Calcd for [M]+
D
(90.2% ee). The ee was determined by HPLC (Chiralcel AD, 1 mL/
min, 100/5 hexane/i-PrOH, λ = 254 nm, retention time: (S) 9.47 min,
(R) 10.84 min.
Benzhydryl (S)-3-Acetoxy-2-methylenebutanoate (5b). Colorless
1
oil (33.1 mg, 51% yield). H NMR (400 MHz, CDCl3): δ 7.36−7.29
(m, 10H), 6.97 (s, 1H), 6.42 (s, 1H), 5.88 (s, 1H), 5.84−5.75 (m,
1H), 2.00 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 168.8, 163.3, 140.1, 139.0, 138.9, 127.5, 127.0, 126.0(8),
126.0(6), 124.5, 76.5, 67.2, 20.1, 18.9; HRMS (EI-TOF): Calcd for
C23H26O4: 366.1831, found: 366.1834. (S)-4g: [α]25 = −9.7° (c
D
0.01, CHCl3) (91.0% ee). The ee was determined by HPLC (Chiralcel
AD, 1 mL/min, 40/1 hexane/i-PrOH, λ = 254 nm, retention time: (S)
16.18 min, (R) 19.45 min.
[M]+ C20H20O4: 324.1362, found: 324.1365. (S)-5b: [α]25 = −11.9°
D
(c 0.01, CHCl3) (84.2% ee). The ee was determined by HPLC
(Chiralcel AD, 1 mL/min, 40/1 hexane/i-PrOH, λ = 254 nm,
retention time: (R) 12.95 min, (S) 13.96 min.
Benzhydryl (S)-2-(Cyclohexyl(propionyloxy)methyl)acrylate (4h).
White solid (33.3 mg, 41% yield), mp 70−71 °C. 1H NMR (400 MHz,
CDCl3): δ 7.45−7.28 (m, 10H), 6.95 (s, 1H), 6.42 (s, 1H), 5.75 (s,
1H), 5.52 (d, J = 5.8 Hz, 1H), 2.41−2.28 (m, 2H), 1.79−1.48 (m,
6H), 1.19−1.06 (m, 6H), 1.03−0.91 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 172.4, 163.5, 139.1, 139.0, 138.3, 127.5, 127.0, 126.9, 126.2,
125.9, 125.6, 76.5, 74.8, 39.9, 28.5, 26.7(1), 26.6(7), 25.2, 25.0, 24.9,
8.1; HRMS (EI-TOF): Calcd for [M]+ C26H30O4: 406.2144, found:
406.2145. The ee was determined by HPLC (Chiralcel AD, 1 mL/min,
40/1 hexane/i-PrOH, λ = 254 nm, retention time: (S) 18.74 min, (R)
22.91 min.
Benzhydryl (S)-2-Methylene-3-(propionyloxy)butanoate (4b).
1
Colorless oil (34.5 mg, 51% yield). H NMR (400 MHz, CDCl3): δ
7.41−7.22 (m, 10H), 6.97 (s, 1H), 6.41 (s, 1H), 5.87 (s, 1H), 5.85−
5.76 (m, 1H), 2.40−2.15 (m, 2H), 1.41 (d, J = 6.4 Hz, 3H), 1.10 (t, J =
7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 172.1, 163.3, 140.2,
138.9(9), 138.9(5), 127.5, 127.0, 126.9, 126.0(7), 126.0(5), 124.4,
76.5, 67.0, 26.7, 18.9, 8.0; HRMS (EI-TOF): Calcd for [M]+
C21H22O4: 338.1518, found: 338.1516. (S)-4b: [α]25 = −10.7° (c
D
0.01, CHCl3) (88.5% ee). The ee was determined by HPLC (Chiralcel
AD, 1 mL/min, 40/1 hexane/i-PrOH, λ = 254 nm, retention time: (S)
13.88 min, (R) 15.80 min.
Benzhydryl (S)-2-Methylene-5-phenyl-3-(propionyloxy)-
pentanoate (4i). White solid (44.5 mg, 52% yield), mp 43−45 °C.
H
DOI: 10.1021/acs.joc.5b00073
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H NMR (400 MHz, CDCl3): δ 7.44−7.04 (m, 16H), 6.96 (s, 1H),
6.43 (s, 1H), 5.83 (s, 1H), 5.79−5.72 (m, 1H), 2.71−2.57 (m, 2H),
2.40−2.25 (m, 2H), 2.19−1.91 (m, 2H), 1.14 (t, J = 7.5 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 172.2, 163.2, 140.1, 139.1, 138.9(4),
138.8(9), 127.5, 127.4, 127.3, 127.0, 126.9, 126.2, 125.9, 124.9, 76.5,
70.4, 34.8, 30.8, 26.6, 8.1; HRMS (ESI-TOF): Calcd for [M + NH4]+
Benzhydryl (S)-5-(Benzyloxy)-2-methylene-3-(propionyloxy)-
pentanoate (4o). Colorless oil (54.0 mg, 59% yield). 1H NMR
(400 MHz, CDCl3): δ 7.48−7.22 (m, 15H), 6.95 (s, 1H), 6.40 (s, 1H),
5.87 (dd, J = 8.5, 4.1 Hz, 1H), 5.83 (s, 1H), 4.48−4.37 (m, 2H), 3.59−
3.37 (m, 2H), 2.36−2.20 (m, 2H), 2.18−2.07 (m, 1H), 2.06−1.93 (m,
1H), 1.09 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 172.1,
163.2, 139.1, 139.0, 137.3, 127.5, 127.3, 126.9(4), 126.8(8), 126.6,
126.5, 126.1, 125.9, 125.1, 76.5, 71.9, 68.5, 65.3, 33.4, 26.6, 8.0; HRMS
(ESI-TOF): Calcd for [M + Na]+ C29H30O5Na: 481.1991, found:
481.1992. (S)-4o: [α]25D = −7.9° (c 0.03, CHCl3) (52.5% ee). The ee
was determined by HPLC (Chiralcel AS, 1 mL/min, 100/5 hexane/i-
PrOH, λ = 254 nm, retention time: (R) (S) 5.68 min, 6.46 min.
Benzhydryl (S)-5-((tert-Butyldimethylsilyl)oxy)-2-methylene-3-
(propionyloxy)pentanoate (4p). Colorless oil (48.2 mg, 50% yield).
1H NMR (400 MHz, CDCl3): δ 7.43−7.27 (m, 10H), 6.97 (s, 1H),
C28H32NO4: 446.2331, found: 446.2335. (S)-4i: [α]25 = −13.0° (c
D
0.01, CHCl3) (82.6% ee). The ee was determined by HPLC (Chiralcel
AS, 1 mL/min, 99.5/0.5 hexane/i-PrOH, λ = 254 nm, retention time:
(S) 9.33 min, (R) 13.71 min.
Methyl (S)-2-Methylene-5-phenyl-3-(propionyloxy)pentanoate
(4j). Colorless oil (25.9 mg, 47% yield). 1H NMR (400 MHz,
CDCl3): δ 7.42−7.03 (m, 5H), 6.30 (s, 1H), 5.78 (s, 1H), 5.67 (dd, J
= 8.1, 4.0 Hz, 1H), 3.76 (s, 3H), 2.81−2.57 (m, 2H), 2.35 (dd, J =
15.1, 7.6 Hz, 2H), 2.15−1.96 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 172.3, 164.7, 140.2, 139.1, 127.4, 127.3,
125.0, 124.2, 70.3, 50.9, 34.9, 30.7, 26.7, 8.1; HRMS (ESI-TOF):
Calcd for [M + Na]+ C16H20O4Na: 299.1259, found: 299.1258. (S)-4j:
6.41 (s, 1H), 5.88−5.79 (m, 2H), 3.74−3.55 (m, 2H), 2.43−2.21 (m,
2H), 2.10−1.81 (m, 2H), 1.12 (t, J = 7.6 Hz, 3H), 0.86 (s, 9H), 0.00
(s, 6H); 13C NMR (100 MHz, CDCl3): δ 172.1, 163.2, 139.3, 139.0,
127.5, 126.9(4), 126.8(7), 126.2, 126.0, 125.1, 76.4, 68.3, 58.3, 36.2,
26.7, 24.9, 17.2, 8.0, −6.4(8), −6.5(1); HRMS (ESI-TOF): Calcd for
[α]25 = +16.2° (c 0.01, CHCl3) (79.1% ee). The ee was determined
D
by HPLC (Chiralcel AS, 1 mL/min, 60/1 hexane/i-PrOH, λ = 254
nm, retention time: (S) 5.74 min, (R) 6.70 min.
[M + Na]+ C28H38O5NaSi: 505.2386, found: 505.2387. (S)-4p: [α]25
D
= −3.6° (c 0.01, CHCl3) (85.1% ee). The ee was determined by
HPLC (Chiralcel AD, 1 mL/min, 40/1 hexane/i-PrOH, λ = 254 nm,
retention time: (R) 5.60 min, (S) 6.46 min.
Naphthalen-1-ylmethyl (S)-2-Methylene-3-(propionyloxy)-
1
butanoate (4k). Colorless oil (25.6 mg, 41% yield). H NMR (400
MHz, CDCl3): δ 8.03 (d, J = 8.2 Hz, 1H), 7.94−7.81 (m, 2H), 7.62−
7.40 (m, 4H), 6.29 (s, 1H), 5.81 (s, 1H), 5.74 (q, J = 6.4 Hz, 1H), 5.67
(s, 2H), 2.37−2.17 (m, 2H), 1.37 (d, J = 6.4 Hz, 3H), 1.09 (t, J = 7.5
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 172.1, 164.2, 140.2, 132.7,
130.6, 130.2, 128.3, 127.7, 126.5, 125.6, 124.9, 124.2, 124.1, 122.5,
67.0, 63.9, 26.7, 19.1, 8.0; HRMS (EI-TOF): Calcd for [M]+
Benzhydryl (S)-3-(Propionyloxy)butanoate (4q). Colorless oil
1
(29.3 mg, 45% yield). H NMR (400 MHz, CDCl3): δ 7.41−7.22
(m, 10H), 6.90 (s, 1H), 5.38−5.28 (m, 1H), 2.75 (dd, J = 15.5, 8.0 Hz,
1H), 2.62 (dd, J = 15.5, 5.3 Hz, 1H), 2.24−1.99 (m, 2H), 1.28 (d, J =
6.3 Hz, 3H), 1.01 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
172.5, 168.2, 139.0, 127.5, 126.9, 126.1(4), 126.1(0), 76.1, 66.2, 40.1,
26.6, 18.9, 7.9; HRMS (EI-TOF): Calcd for [M]+ C20H22O4:
C19H20O4: 312.1362, found: 312.1363. (S)-4k: [α]25 = −14.9° (c
D
0.03, CHCl3) (84.0% ee). The ee was determined by HPLC (Chiralcel
IF, 1 mL/min, 80/1 hexane/i-PrOH, λ = 254 nm, retention time: (R)
14.27 min, (S) 15.81 min.
326.1518, found: 326.1516. (S)-4q: [α]25 = +5.6° (c 0.02, CHCl3)
D
(84.0% ee). The ee was determined by HPLC (Chiralcel OJ, 1 mL/
min, 90/10 hexane/i-PrOH, λ = 254 nm, retention time: (S) 16.17
min, (R) 19.41 min.
5. Preparation of Methyl Ester (R)-6 and (R)-7. A mixture of ester
1b (350 mg, 1.24 mmol) and K2CO3 (86 mg, 0.62 mmol) in dried
Phenethyl (S)-2-Methylene-3-(propionyloxy)butanoate (4l). Col-
orless oil (24.9 mg, 45% yield). 1H NMR (400 MHz, CDCl3): δ 7.44−
7.14 (m, 5H), 6.24 (s, 1H), 5.79 (s, 1H), 5.74−5.65 (m, 1H), 4.38 (t, J
= 6.7 Hz, 2H), 2.99 (t, J = 6.7 Hz, 2H), 2.33 (q, J = 7.5 Hz, 2H), 1.34
(d, J = 6.3 Hz, 3H), 1.14 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3):δ 172.1, 164.2, 140.4, 136.7, 127.9, 127.5, 125.6, 123.6, 67.0,
64.4, 34.1, 26.8, 19.2, 8.1; HRMS (EI-TOF): Calcd for [M]+
C16H20O4: 276.1362, found: 276.1353. (S)-4l: [α]25 = −11.9° (c
D
0.01, CHCl3) (90.4% ee). The ee was determined by HPLC (Chiralcel
IF, 1 mL/min, 90/10 hexane/i-PrOH, λ = 254 nm, retention time: (R)
5.42 min, (S) 6.16 min.
MeOH (6 mL) was stirred at room temperature for 1 h. The reaction
mixture was neutralized by the addition of Dowex 50 (H+ form),
filtered, concentrated, and purified by silica gel column chromatog-
raphy (petroleum/EtOAc = 6/1) to give product 6 (130.7 mg, 81%)
as a colorless oil.
Benzhydryl (R)-4-(Benzyloxy)-2-methylene-3-(propionyloxy)-
1
butanoate (4m). Colorless oil (54.2 mg, 61% yield). H NMR (400
MHz, CDCl3) δ 7.34−7.11 (m, 15H), 6.87 (s, 1H), 6.43 (s, 1H),
6.00−5.91 (m, 2H), 4.42 (dd, J = 36.0, 12.2 Hz, 2H), 3.65−3.53 (m,
2H), 2.39−2.20 (m, 2H), 1.07 (t, J = 7.6 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 172.2, 163.0, 138.9, 136.9, 136.1, 127.5, 127.3, 127.0,
126.9, 126.6(1), 126.5(5), 126.5(3), 126.2, 126.0, 76.6, 72.0, 69.9,
69.5, 26.6, 8.0; HRMS (ESI-TOF): Calcd for [M + Na]+ C28H28O5Na:
Methyl (R)-3-Hydroxy-2-methylenebutanoate (6).8a Colorless oil
(130.7 mg, 81% yield). 1H NMR (400 MHz, CDCl3): δ 6.22 (s, 1H),
5.86−5.80 (m, 1H), 4.67−4.58 (m, 1H), 3.80 (s, 3H), 2.63 (s, 1H),
1.40 (d, J = 6.5 Hz, 3H). (R)-6: [α]25 = +17.4° (c 0.01, CHCl3)
D
467.1834, found: 467.1834. (R)-4m: [α]25 = −3.2° (c 0.01, CHCl3)
(99.2% ee); (ee1b= 99.2%). The ee was determined by HPLC
(Chiralcel OD, 1 mL/min, 40/1 hexane/i-PrOH, λ = 220 nm,
retention time: (R) 11.68 min, (S) 13.36 min.
D
(29.4% ee). The ee was determined by HPLC (Chiralcel AS, 1 mL/
min, 90/10 hexane/i-PrOH, λ = 254 nm, retention time: (R) 5.42 min,
(S) 6.96 min.
Benzhydryl (R)-4-((tert-Butyldimethylsilyl)oxy)-2-methylene-3-
(propionyloxy)butanoate (4n). Colorless oil (45.9 mg, 49% yield).
1H NMR (400 MHz, CDCl3): δ 7.45−7.26 (m, 10H), 6.97 (s, 1H),
6.49 (s, 1H), 5.91 (s, 1H), 5.79 (dd, J = 6.2, 3.5 Hz, 1H), 3.84 (dd, J =
11.1, 3.5 Hz, 1H), 3.72 (dd, J = 11.1, 6.2 Hz, 1H), 2.44−2.28 (m, 2H),
1.14 (t, J = 7.6 Hz, 3H), 0.84 (s, 9H), −0.01 (s, 3H), −0.02 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 172.1, 163.1, 139.0, 136.2, 127.5(2),
127.5(1), 127.0, 126.9, 126.7, 126.2, 126.0, 76.5, 71.6, 63.1, 26.7, 24.7,
17.2, 8.0, −6.4(6), −6.4(7); HRMS (ESI-TOF): Calcd for [M + Na]+
C27H36O5NaSi: 491.2230, found: 491.2229. (R)-4n: [α]25D = −1.1° (c
0.02, CHCl3) (78.1% ee). The ee was determined by HPLC (Chiralcel
AD, 1 mL/min, 100/5 hexane/i-PrOH, λ = 254 nm, retention time:
(S) 5.36 min, (R) 6.05 min.
I
DOI: 10.1021/acs.joc.5b00073
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
A mixture of ester 1o (560 mg, 1.39 mmol) and NaOMe (15 mg,
0.28 mmol) in dried MeOH (7 mL) was stirred at room temperature
for 4 h. The reaction mixture was neutralized by the addition of Dowex
50 (H+ form), filtered, concentrated, and purified by silica gel column
chromatography (petroleum/EtOAc = 6/1) to give product 7 (299.2
mg, 86%) as a colorless oil.
Methyl (R)-5-(Benzyloxy)-3-hydroxy-2-methylenepentanoate
(7).9a Colorless oil (299.2 mg, 86% yield). 1H NMR (400 MHz,
CDCl3) δ 7.40−7.29 (m, 5H), 6.28 (s, 1H), 5.96−5.89 (m, 1H),
4.76−4.63 (m, 1H), 4.52 (s, 2H), 3.75 (s, 3H), 3.72−3.64 (m, 2H),
3.61 (d, J = 5.0 Hz, 1H), 2.12−1.99 (m, 1H), 1.93−1.79 (m, 1H).
6. Transesterification of (R)-1i. The procedure of the trans-
esterification of (R)-1i (74.4 mg, 0.2 mmol) was employed according
68, 3844−3848. (f) Fu, G. C. Acc. Chem. Res. 2004, 37, 542−547.
(g) Yamada, S.; Misono, T.; Iwai, Y. Tetrahedron Lett. 2005, 46, 2239−
2242. (h) Diez, D.; Gil, M. J.; Moro, R. F.; Garrido, N. M. Tetrahedron:
Asymmetry 2005, 16, 2980−2985. (i) Connon, S. J.; Dalaigh, C. O.;
Hynes, S. J.; Maher, D. J. Org. Biomol. Chem. 2005, 3, 981−984.
(j) Mizuta, S.; Ohtsubo, Y.; Tsuzuki, T.; Fujimoto, T.; Yamamoto, I.
Tetrahedron Lett. 2006, 47, 8227−8229. (k) Nguyen, H. V.; Motevalli,
M.; Richards, C. J. Synlett 2007, 725−728. (l) Kundig, E. P.; Carcia, A.
̈
E.; Lomberget, T.; Garcia, P. P.; Romanens, P. Chem. Commun. 2008,
3519−3521. (m) De, C. K.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc.
2009, 131, 17060−17061. (n) Hrdina, R.; Muller, C. E.; Schreiner, P.
̈
R. Chem. Commun. 2010, 46, 2689−2690. (o) Carbery, D. R.; Crittall,
M. R.; Rzepa, H. S. Org. Lett. 2011, 13, 1250−1253.
(4) (a) Birman, V. B.; Uffman, E. W.; Hui, J.; Li, X. M.; Kilbane, C. J.
J. Am. Chem. Soc. 2004, 126, 12226−12227. (b) Birman, V. B.; Jiang,
H. Org. Lett. 2005, 7, 3445−3447. (c) Birman, V. B.; Li, X. Org. Lett.
2006, 8, 1351−1354. (d) Birman, V. B.; Li, X. Org. Lett. 2008, 10,
1115−1118. (e) Zhang, Y.; Birman, V. B. Adv. Synth. Catal. 2009, 351,
2525−2529. (f) Li, X.; Jiang, H.; Uffman, E. W.; Guo, L.; Zhang, Y.;
Yang, X.; Birman, V. B. J. Org. Chem. 2012, 77, 1722−1737.
(5) (a) Hu, B.; Meng, M.; Wang, Z.; Du, W.; Fossey, J. S.; Hu, X.;
Deng, W.-P. J. Am. Chem. Soc. 2010, 132, 17041−17044. (b) Wang, Z.;
Ye, J.; Wu, R.; Liu, Y.-Z.; Fossey, J. S.; Cheng, J.; Deng, W.-P. Catal.
Sci. Technol. 2014, 4, 1909−1913.
(6) (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237−6240.
(b) Kitamura, M.; Kasahara, I.; Manabe, K.; Noyori, R.; Takaya, H. J.
Org. Chem. 1988, 53, 708−710. (c) Bellemin-Laponnaz, S.; Tweddell,
J.; Ruble, J. C.; Breitling, F. M.; Fu, G. C. Chem. Commun. 2000,
1009−1010. (d) Vedejs, E.; Mackay, J. A. Org. Lett. 2001, 3, 535−536.
to the preparation of compound 7. (R)-1j: Colorless oil (35 mg, 80%
yield). [α]25 = +26.8° (c 0.01, CHCl3) (99.6% ee); (ee1i = 99.6%).
D
ASSOCIATED CONTENT
■
S
* Supporting Information
́
́
aigh, C. O.; Connon, S. J. J. Org. Chem. 2007, 72, 7066−7069.
(7) Dal
(8) (a) Brzezinski, L. J.; Rafel, S.; Leahy, J. W. J. Am. Chem. Soc. 1997,
119, 4317−4318. (b) Frezza, M.; Balestrino, D.; Soulere, L.;
Copies of 1H and 13C NMR spectra and HPLC data of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
̀
Reverchon, S.; Queneau, Y.; Forestier, C.; Doutheau, A. Eur. J. Org.
Chem. 2006, 4731−4736. (c) Kamal, A.; Krishnaji, T.; Reddy, P. V.
Tetrahedron Lett. 2007, 48, 7232−7235. (d) Singh, S. K.; Singh, G. B.;
Byri, V. K.; Satish, B.; Dhamjewar, R.; Gopalan, B. Synth. Commun.
2008, 38, 456−464. (e) Sarkar, S. M.; Wanzala, E. N.; Shibahara, S.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Chem. Commun. 2009,
5907−5909. (f) Krishna, P. R.; Kadiyala, R. R. Tetrahedron Lett. 2010,
51, 4981−4983.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: xxyu@ecust.edu.cn.
■
*E-mail: weiping_deng@ecust.edu.cn.
Notes
The authors declare no competing financial interest.
(9) (a) Bailey, M.; Marko,
32, 2687−2690. (b) Bailey, M.; Staton, I.; Ashton, P. R.; Marko,
Ollis, W. D. Tetrahedron: Asymmetry 1991, 2, 495−509. (c) Micu
́
I. E.; Ollis, W. D. Tetrahedron Lett. 1991,
I. E.;
ch,
́
ACKNOWLEDGMENTS
̌
́
■
We are grateful for financial support from the Fundamental
Research Funds for the Central Universities, the National
Natural Science Foundation of China (no. 21372074).
̌ ́
P.; Fisera, L.; Cyranski, M. K.; Krygowski, T. M. Tetrahedron Lett.
1999, 40, 167−170. (d) Adam, W.; Groer, P.; Humpf, H.-U.; Saha-
̌
Moller, C. R. J. Org. Chem. 2000, 65, 4919−4922. (e) Svenda, J.;
̈
Myers, A. G. Org. Lett. 2009, 11, 2437−2440. (f) Lumbroso, A.;
Cooke, M. L.; Breit, B. Angew. Chem., Int. Ed. 2013, 52, 1890−1932.
(10) (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003,
103, 811−891. (b) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem.
Rev. 2010, 110, 5447−5674.
REFERENCES
■
(1) (a) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev.
2003, 103, 2985−3012. (b) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed.
2005, 44, 3974−4001. (c) Wurz, R. P. Chem. Rev. 2007, 107, 5570−
5595. (d) Spivey, A. C.; Arseniyadis, S. Top. Curr. Chem. 2010, 291,
233−280. (e) Pellissier, H. Adv. Synth. Catal. 2011, 353, 1613−1666.
(11) (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J.
Am. Chem. Soc. 1999, 121, 10219−10220. (b) Shi, M.; Jiang, J.-K.
Tetrahedron: Asymmetry 2002, 13, 1941−1947. (c) Nakano, A.;
Ushiyama, M.; Iwabuchi, Y.; Hatakeyama, S. Adv. Synth. Catal. 2005,
347, 1790−1796. (d) Nakano, A.; Kawahara, S.; Akamatsu, S.;
Morokuma, K.; Nakatani, M.; Iwabuchi, Y.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Tetrahedron 2006, 62, 381−389. (e) Nakano, A.;
Takahashi, K.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2006, 8, 5357−
5360. (f) Nakamoto, Y.; Urabe, F.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Chem.Eur. J. 2013, 19, 12653−12656.
(f) Muller, C. E.; Schreiner, P. R. Angew. Chem., Int. Ed. 2011, 50,
̈
6012−6042.
(2) (a) Vedejs, E.; Daugulis, O.; Diver, S. T. J. Org. Chem. 1996, 61,
430−431. (b) Vedejs, E.; Chen, X. H. J. Am. Chem. Soc. 1996, 118,
1809−1810. (c) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem.
Soc. 1997, 119, 1492−1493. (d) Ruble, J. C.; Tweddell, J.; Fu, G. C. J.
Org. Chem. 1998, 63, 2794−2795. (e) Fu, G. C. Acc. Chem. Res. 2000,
33, 412−420.
(12) (a) Shiina, I.; Nakata, K.; Ono, K.; Sugimoto, M.; Sekiguchi, A.
Chem.Eur. J. 2010, 16, 167−172. (b) Nakata, K.; Sekiguchi, A.;
Shiina, I. Tetrahedron: Asymmetry 2011, 22, 1610−1619. (c) Nakata,
K.; Gotoh, K.; Ono, K.; Futami, K.; Shiina, I. Org. Lett. 2013, 15,
1170−1173. (d) Shiina, I.; Ono, K.; Nakahara, T. Chem. Commun.
2013, 49, 10700−10702.
(3) (a) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem.
Soc. 1997, 119, 3169−3170. (b) Vedejs, E.; Daugulis, O. J. Am. Chem.
Soc. 1999, 121, 5813−5814. (c) Spivey, A. C.; Fekner, T.; Spey, S. E. J.
Org. Chem. 2000, 65, 3154−3159. (d) Gopeland, G. T.; Miller, S. J. J.
Am. Chem. Soc. 2001, 123, 6496−6502. (e) Priem, G.; Pelotier, B.;
Macdonald, S. J. F.; Anson, M. S.; Campbell, I. B. J. Org. Chem. 2003,
J
DOI: 10.1021/acs.joc.5b00073
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(13) (a) Adam, W.; Hoch, U.; Saha-Moller, C. R.; Schreier, P. Angew.
̈
Chem., Int. Ed. 1993, 32, 1737−1739.
(14) Enantioselectivity in kinetic resolutions is usually expressed in
terms of a selectivity factor (S) defined as the ratio between reaction
rates of the fast- and the slow-reacting enantiomers of the starting
racemate: S = kfast/kslow. If the starting material is racemic, both the
conversion (C) and the selectivity factors can be calculated from the ee
values of the product and the recovered substrate according to the
following Kagan’s equations: C = eeSM/(eeSM + eePR); s = ln[(1 − C)
(1 − eeSM)]/ln[(1− C)(1 + eeSM)].
(15) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249−330.
(16) Nudelman, A.; Kelner, R.; Broida, N.; Gottlieb, H. E. Synthesis
1989, 5, 387−388.
(17) Yang, K.-S.; Lee, W.-D.; Pan, J.-F.; Chen, K. J. Org. Chem. 2003,
68, 915−919.
K
DOI: 10.1021/acs.joc.5b00073
J. Org. Chem. XXXX, XXX, XXX−XXX