Facile synthesis of α-methylidene-γ-butyrolactones: Intramolecular Rauhut-Currier reaction promoted by chiral acid-base organocatalysts

Article abstract of DOI:10.1016/j.tet.2012.11.046

The acid-base organocatalyzed intramolecular Rauhut-Currier (RC) reaction of the dienone enolates has been developed. The enantioselective RC process produces the highly functionalized α-methylidene-γ-butyrolactones as a single diastereomer with up to 98% ee.

Full text of DOI:10.1016/j.tet.2012.11.046

Tetrahedron 69 (2013) 1202e1209
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile synthesis of a-methylidene-g-butyrolactones: intramolecular
RauhuteCurrier reaction promoted by chiral acidebase
organocatalysts
a
a
a,
Shinobu Takizawa , Tue Minh-Nhat Nguyen , Andre Grossmann b, Michitaka Suzuki a, Dieter Enders b,
ꢀ
,
Hiroaki Sasai a
*
a The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan
b Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 October 2012
Received in revised form 11 November 2012
Accepted 12 November 2012
Available online 28 November 2012
The acidebase organocatalyzed intramolecular RauhuteCurrier (RC) reaction of the dienone enolates has
been developed. The enantioselective RC process produces the highly functionalized
butyrolactones as a single diastereomer with up to 98% ee.
a-methylidene-g-
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
RauhuteCurrier
Enantioselective
Organocatalysts
a
-Methylidene-g-butyrolactones
Intramolecular
1. Introduction
cysteine-derived thiolates,7a rhenium-phosphine complexes,7b
prolinol derivatives with AcOH,7c or valine-derived phosphino-
thioureas7d as catalysts, respectively. Gu and Xiao extended this
reaction to nitroolefins.8 Scheidt and Shi presented the in-
termolecular reaction of silyloxyallenes and allenoates catalyzed by
Enantioselective organocatalysis has been recognized as an
environmentally benign and practical methodology for asymmetric
organic synthesis.1 Among the achievements, CeC bond-forming
reactions using chiral organocatalysts play an outstanding role in
enabling highly selective syntheses of biologically important
Sc(OTf)3$(R,R)-Ph-Pybox or
b
-ICD.9 More recently, asymmetric
[4þ2] annulations via aza-RC reaction have been realized with
chiral amino phosphine catalyst.10 Highly selective construction of
complex frameworks via the enantioselective RC reaction has been
a challenge in asymmetric synthetic chemistry.
compounds.2 The RauhuteCurrier (RC) reaction, in which two
a,b-
unsaturated carbonyl compounds are used as the substrates, pro-
vides a readily access to -substituted enones, where one of the
a
a,b-
unsaturated carbonyl compounds acts as a latent enolate (Fig. 1, Eq.
1).3,4 In contrast to the related MoritaeBayliseHillman (MBH) and
aza-MBH reactions,5 where the latent enolate reacts with another
carbonyl compound or imine (Eqs. 2 and 3), the RC reaction lacks
We envisioned that desymmetrization of the prochiral dienones
2, which are easily accessible from readily available phenols,11 via
the RC reaction is a straightforward and atom economical way to
prepare -methylidene-
a
g a-meth-
-butyrolactones 1 (Fig. 2).12 The
reactivity and selectivity. The use of two different
a
,b
-unsaturated
ylidene-g-butyrolactone skeleton exhibiting various biological ac-
carbonyl compounds on the RC reaction led to a mixture of the
homo- and hetero-couplings. Therefore, until now, limited num-
bers of attractive systems have been developed for the RC re-
action.6,7 The first breakthrough in the enantioselective RC reaction
was reported by Miller in 2007 with further contributions by Gla-
dysz, Christman and Wu. These groups succeeded in the enantio-
selective RC reaction of bis(enones) or enal-enones utilizing
tivities is a common to a vast number of natural products, such as
paeonilactone B (3), calealactone C (4) and tricyclic compounds 5
and 6 (Fig. 3).13
We have also developed several highly efficient MBH-type re-
actions promoted by acidebase organocatalysts (Fig. 4).14 An ap-
propriate positions of both the Brønsted acid (BA) and the Lewis
base (LB) units on one chiral back bone could facilitate a synergistic
cooperation to generate the designated chiral enolate I, the enan-
tioselective RC reaction of 2 (Fig. 2) would take place with high
chemo-, diastereo- and enantioselectivities. In this manuscript, we
* Corresponding author. E-mail address: sasai@sanken.osaka-u.ac.jp (H. Sasai).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.046

S. Takizawa et al. / Tetrahedron 69 (2013) 1202e1209
1203
Fig. 1. Comparison of RauhuteCurrier reaction with MBH type reactions.
Fig. 2. Retrosynthesis of a-methylidene-g-butyrolactones 1 via the RC process.
Fig. 4. Acidebase organocatalysts for the aza-MBH reactions and the estimated key
intermediate I for the RC reaction.
and 2). In the absence of phenol, PPh3 rarely catalyze the cyclo-
isomerization affording a low yield of 1a (entry 7). Reducing a LB
catalyst loading to 20 mol % still maintained moderate yield (entry
8), however reduction of a BA catalyst (20 mol %) led to a decreasing
the reaction rate (entry 9). Among the solvents tested, halogenated
solvents (entries 1, 10 and 11), toluene (entry 12) and MeCN (entry
13) provided 1a in moderate to good yields. When (S)-BINOL was
used as a chiral Brønsted acid, no asymmetric induction onto 1a
was observed (entry 15).17
Fig. 3.
a-Methylidene-g-butyrolactones isolated from natural sources.
report the details of the acidebase organocatalyzed intramolecular
RC reaction of 2.15 The present enantioselective RC process pro-
Next, we tested chiral organocatalysts for the RC reaction of 2a
duces the highly functionalized
a-methylidene-g-butyrolactones 1
as shown in Table 2. b-ICD, catalysts 7e9, and 12e15, some of which
as a single diastereomer with up to 98% ee.
are known to mediate the enantioselective MBH-type pro-
cesses,5,14,18 showed no activity (Table 2, entry 1). (S)-BINAP and
(S)-MOP could give the product but in low yields with low or no
selectivity (entries 2 and 3). The ferrocenyl phosphine (Rc,Sp)-PPFA
promoted the reaction in 72% yield and 20% ee (entry 4), whereas
(Sc,Rp)-BPPFA and (Sc,Rp)-BPPFOH exhibited low catalytic activities
(entries 5 and 6). During this screening process, the chiral orga-
nocatalysts 16 possessing a highly nucleophilic phosphine due to
their connection at the phosphorus atom to a primary carbon
caught our attention.5h As expected, (R)-16a was able to promote
the RC reaction to afford 1a in 52% yield and 60% ee (entry 7).
In contrast, no catalytic activity was observed when using the
phosphinothiourea catalyst 16b7d,19 (entry 8). These results can be
attributed to the over-stabilization of the enolate intermediate Ia
by relatively high acidic NeH in the thiourea catalyst or the
2. Results and discussion
As the first step in the development of the designated RC re-
action, achiral LB catalysts were evaluated using 2a as a pro-
totypical substrate (Table 1). The MBH reaction is known to be
accelerated in the presence of a BA.5 Given the similarity of the
MBH and RC reactions, various BAs were added to the reaction of 2a
in order to increase the reaction rate. Among the LBs (DMAP, DBU or
DABCO) and BAs (TFA, PhCO2H, thiourea 10 or phosphoric acid 11)
examined (Table 1, entries 1e6), the combination of PPh3
(100 mol %) and phenol (C6H5OH)16 (50 mol %) or C2H5NHTs
(50 mol %) was found to efficiently promote the reaction to give the
desired product 1a in 81% yield, 90% yield, respectively (entries 1

1204
S. Takizawa et al. / Tetrahedron 69 (2013) 1202e1209
Table 1
Table 2
Achiral LBeBA catalyzed RC reaction
Enantioselective RC reaction using an organocatalyst
Entry
Chiral organocatalyst
-ICD, 7e9 or 12e15
(S)-BINAP
(S)-MOP
(Rc,Sp)-PPFA
(Sc,Rp)-BPPFA
(Sc,Rp)-BPPFOH
(R)-16a
(R)-16b
(S)-16c
(S)-16d
(S)-16d
Time [h]
Yielda [%]
ee [%]b
1
2
3
4
5
6
7
8
b
48
18
22
18
19
19
18
19
24
19
48
24
24
No reaction
6
d
20
rac
20
9
Entry LB catalyst
BA catalyst
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
PPh3
PPh3
C6H5OH
C2H5NHTs
CH2Cl2
CH2Cl2
CH2Cl2
81
90
<10
<10
32
29
16
63
43
53
60
72
65
16
72
13
3
52
Trace
55
77
80
87
99f
DMAP, DBU or DABCO C6H5OH
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
TFA or PhCO2H CH2Cl2
10
11
None
C6H5OH
C6H5OHb
C6H5OH
C6H5OH
C6H5OH
C6H5OH
C6H5OH
(S)-BINOL
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3Cl
(CH2Cl2)2
Toluene
MeCN
60
d
45
80
93
93
98
9
b
10
11c
12c,d
13c,d,e
9
10
11
12
13
14
15
(S)-16d
(S)-16d
a
Determined by 1H NMR.
Determined by HPLC (Daicel Chiralpak IC).
At 0 ꢀC.
Without phenol.
In CHCl3.
Isolated yield.
b
c
d
e
f
THF, MeOH or H2O Trace
CH2Cl2
37c
a
Determined by 1H NMR.
20 mol %.
rac-1a was obtained.
b
c
formation of protonated species IIa from the enolate Ia (Scheme 1).
In fact, the 31P NMR spectroscopic data of 2a with PPh3 (1 equiv) or
16d (1 equiv) and an excess amount of phenol (10 equiv) made
visible a signal of phosphonium enone II (IIb: 24.4 ppm, IIc:
28.9 ppm) via the corresponding intermediate I. The structure of
IIb,c was also supported by the 1H and 13C NMR spectroscopic data
and ESI-HRMS. A few hours later compound 17 obtained as a de-
composition product from II was observed.
Finally the acidebase organocatalyst (S)-16d20 was found to
yield acceptable outcome with over 80% ees (entries 10e13). A
lower reaction temperature led to a drastic improvement in the
enantioselectivity (entry 11). In the absence of phenol, a higher
reaction rate was observed and the high enantioselectivity was
maintained (entry 12). The best result (99% isolated yield, 98% ee)
was obtained when the reaction was performed in CHCl3 at 0 ꢀC in
the absence of phenol (entry 13).
challenging in organic synthesis.23 When 2o was applied for this
enantioselective reaction, the corresponding lactone 1o was ob-
tained in 56% yield and 70% ee (Table 3, entry 1). In order to
improve the yield and enantioselectivity, various amounts of BAs
were added as extraneous proton-shuttle reagents. The increasing
amount of phenol led to a significantly increasing of the ee value
of 1o to 96%, albeit dropping to lower chemical yields (entries
1e4). Among the BAs tested, sterically less-hindered and electron
rich phenol derivatives, such as 2-naphthol and 4-methoxyphenol
led to 1o in synthetically useful yields with over 90% ee (entries 6
and 12). The recent MBH investigations carried out by Masson
and Zhu showed that the addition of 2-naphthol in aza-MBH re-
With the optimized conditions in hand, we focused on the
substrate scope (Scheme 2). Aliphatic and aromatic substituted
starting materials 2 were successfully cyclized to give
a-methyl-
idene- -butyrolactones 1 in good yields and high enantioselectiv-
g
ities. The lactones were determined to be cis-configured via NOESY
experiments conducted on 1a. In all cases a single diastereomer
was obtained.21 Aliphatic substrates 2bef were cyclized in high
enantioselectivity (92e98% ee), although higher catalyst loading
and longer reaction times (30 mol %, 72 h) had to be used. In-
terestingly, aromatic substituted substrates were more reactive
than aliphatic substrates.22 The reaction of aromatic substituted
substrates 2gel yielded the corresponding products 1gel in good
yields (82e97%) with high enantioselectivities (88e98% ee). How-
ever, no reaction took place to give 1m and 1n when the substrates
2m and 2n with methyl substitutes on the terminal olefin on the
action mediated by b-ICD derivatives led to an improvement of
enantioselectivities via a dual activation mechanism.24 Similarly,
in the presence of achiral BAs in this RC reaction of 2o, a second
Michael reaction may become highly stereoselective via a dual
activation mechanism by (S)-16d and achiral BAs (Scheme 4, in-
termediate I0).
acrylate or
a
-positions of dienone were employed.
The use of disubstituted phenols in the preparation of the
starting materials would lead to racemic dienones 2p and 2q
(Tables 4 and 5). We were intrigued by the opportunity to
The construction of structural motifs bearing two contiguous,
quaternary, stereogenic centers is considered as especially

S. Takizawa et al. / Tetrahedron 69 (2013) 1202e1209
1205
Table 3
Effects of the BA catalysts on RC reaction of 2o
Entry
BA catalyst (xx mol %)
Isolated yield [%]
ee [%]a
1
2
3
4
5
6
7
8
None
C6H5OH (10)
C6H5OH (30)
C6H5OH (50)
4-MeOeC6H4OH (10)
4-MeOeC6H4OH (30)
2-MeOeC6H4OH (30)
2,4,6-Me3eC6H2OH (30)
4-NO2eC6H4OH (30)
(R)- or (S)-BINOL
2-Naphthol (10)
2-Naphthol (30)
56
62
42
5
44
36
45
47
70
74
81
96
89
90
72
74
d
9
Trace
Trace
46
10
11
12
d
89
93
38
a
Determined by HPLC (Daicel Chiralpak IC).
Scheme 1. Stabilization of phosphonium salts.
assembled and subjected to optimized reaction conditions using
(S)-16d. Regarding regioselectivity, intramolecular cyclization oc-
curs exclusively at the less hindered side of the dienone on both
substrates. Although the products and the recovering starting
materials were obtained in good enantioselectivities, de-
composition of 2 led to moderate total yields of (S,S)-1 and (R)-2.
The addition of phenol (Table 4, entries 2 to 4 and Table 5, entry 1)
and 2-naphthol (Table 4, entry 5 and Table 5, entry 2) could im-
prove the enantioselectivity.
investigate the relative propensity to induce cyclization onto the
Michael acceptors in an intramolecular competition (1p versus 1p0
and 1q versus 1q0). As such, racemic substrates 2p and 2q were
To demonstrate the synthetic utility of the highly functionalized
RC product 1a, a variety of transformations were performed
(Scheme 3). The allyl alcohol 17 could be formed by Luche reduction
25
of 1a in the presence of Yb(OTf)3 (step a). Bromination of 1a
followed by elimination formed vinyl bromide 18 (step b).26 Fur-
thermore, the Michael addition of dibenzyl malonate to 1a with
K2CO3 with PPh3 produced the single diastereomer 18 in 67%
yield.10,27
The proposed mechanism of the RC reaction using the chiral
catalyst 16d bearing both Brønsted acid (BA: eNHTs) and Lewis
base (LB: ePPh2) moieties is shown in Scheme 4. First the Michael
addition of the LB moiety to the acrylate unit of 2 generates the
phosphonium enolate I stabilized by the BA, which can react with
one of the olefines on the dienone part. This second Michael pro-
cess forms intermediate III. In order to avoid steric interactions
i
between the Pr-substituent of the chiral catalyst 16d and the R-
substituent in the substrate, the reaction using (S)-16d may afford
the (S,S)-configuration intermediate IIIa. The proton-transfer from
the
anion part in IIIa through the BA moiety results in the formation of
the chiral -methylidene- -butyrolactones 1, along with re-
a-position of a carbonyl group of the lactone to the enolate
a
g
generation of the organocatalyst via retro-Michael reaction. Since
the BA moiety plays an important role to promote the reaction,28
we agree with the report of Miller on the bis(enone) cyclization
that the proton-transfer step is rate determining.7a,e
3. Conclusions
In summary we developed a highly atom economical, chemo-,
diastereoselective approach to the medicinally important cores
a-
methylidene- -butyrolactones via an organocatalytic Rau-
g
huteCurrier (RC) reaction. The Brønsted acidic sulfonamide and
nucleophilic phosphine in 16d cooperatively function to promote
the intramolecular RC process with high enantioselectivities. Fur-
ther details on the reaction mechanism and the application of this
Scheme 2. Scope of the enantioselective RC reaction of 1.a

1206
S. Takizawa et al. / Tetrahedron 69 (2013) 1202e1209
Table 4
RC reaction of racemic 2p with catalyst (S)-16d
Entry
BA catalyst (xx mol %)
Ratio 1p:2p
% Total yields of 1p, 2pa
% ee of (S,S)-1p, (R)-2pb
1
2
3
4
5
None
73:27
71:29
52:48
50:50
40:60
64
62
68
73
76
54, 70
56, 88
86, 60
86, 62
94, 50
C6H5OH (10)
C6H5OH (20)
C6H5OH (30)
2-Naphthol (30)
a
Determined by 1H NMR.
Determined by HPLC (Daicel Chiralpak IC).
b
Table 5
RC reaction of racemic 2q with catalyst (S)-16d
Entry
BA catalyst (xx mol %)
Ratio 1q:2q
% Total yields of 1q, 2qa
% ee of (S,S)-1q, (R)-2qb
1
2
C6H5OH (30)
2-Naphthol (30)
40:60
64:36
66
64
87, 76
88, 72
a
Determined by 1H NMR.
Determined by HPLC (Daicel Chiralpak IC).
b
Scheme 3. Synthetic transformations of (S,S)-1a. (a) Yb(OTf)3 (1.1 equiv), NaBH4
(1.1 equiv), MeOH, 0 ꢀC, 15 min, quant. (dr 77:23, determined by 1H NMR); (b) Br2
(1.05 equiv), CH2Cl2,
0
ꢀC, 30 min, 82%; (c) dibenzyl malonate (1.1 equiv), PPh3
(2.0 equiv), K2CO3 (2.0 equiv), CH2Cl2, rt, 6 h, 67%.
method in natural product synthesis are part of the current re-
search and will be reported in due course.
4. Experimental section
4.1. General information
Scheme 4. Proposed mechanism of the RC reaction.
1H, 13C, 19F, and 31P NMR spectra were recorded with JEOL JMN
LA-400 FT NMR or JNM ECA600 FT NMR (1H NMR 400 MHz, 13C
NMR 100 MHz, 19F NMR 376 MHz, 31P NMR 255 MHz). 1H NMR
spectra are reported as follows: chemical shift in parts per million
JMS-T100LC (JEOL). FAB-MS spectra were obtained with JMS-700
(JEOL). Optical rotations were measured with JASCO P-1030 polar-
imeter. HPLC analyses were performed on a JASCO HPLC system
(JASCO PU 980 pump and UV-975 UV/Vis detector) using a mixture
of hexane and 2-propanol or EtOH as eluents. FT-IR spectra were
recorded on a JASCO FT-IR system (FT/IR4100). Mp was measured
with SHIMADZU DSC-60. Column chromatography on SiO2 was
(d) relative to the chemical shift of CHCl3 at 7.26 ppm, integration,
multiplicities (s¼singlet, d¼doublet, q¼quartet, t¼triplet,
m¼multiplet), and coupling constants (Hertz). 13C NMR spectra
performed with Kishida Silica Gel (63e200
mm). Commercially
reported in ppm (d) relative to the central line of triplet for CDCl3 at
77 ppm CF3CO2H or H3PO4 used as external standards for 19F or 31
P
available organic and inorganic compounds were used without
further purification except for the solvent, which was distilled from
sodium/benzophenone or CaH2.
NMR, respectively. FT-MS spectra were obtained with LTQ Orbitrap
XL (Thermo Fisher Scientific). ESI-MS spectra were obtained with

S. Takizawa et al. / Tetrahedron 69 (2013) 1202e1209
1207
4.2. General procedure for the preparation of dienone (2)
859; 1H NMR (CDCl3):
d
8.28 (s, 1H), 8.14 (d, J¼8.2 Hz, 1H), 7.7 (d,
J¼8.2 Hz, 1H), 7.50 (t, J¼8.2 Hz, 1H), 6.65 (dd, J¼10.5, 1.8 Hz, 1H),
A round bottom flask was charged with a solution of 4-hydroxy-
2,5-cyclohexadien-1-one (2 mmol) in CH2Cl2 (10 mL) followed by
the addition of NEt3 (4 mmol). Acrolyl chloride (4 mmol) was added
dropwise. The reaction mixture was allowed to stir for 10 min at
room temperature. The reaction was then quenched with water,
extracted with CH2Cl2, and dried over Na2SO4. The solvent was
removed in vacuo and the crude product was purified by silica gel
column chromatography using n-hexane/AcOEt as an eluent to give
the desired product 2 as a yellow oil or white solid.
6.38 (d, J¼3.6 Hz, 1H), 6.26 (d, J¼10.1 Hz, 1H), 5.62 (d, J¼2.7 Hz, 1H),
3.47 (m, 1H), 2.84 (d, J¼2.5 Hz, 2H); 13C NMR (CDCl3):
d 193.8, 169.9,
147.9, 142.9, 142.8, 141.4, 132.5, 129.6, 128.2, 124.5, 121.5, 116.9, 93.4,
41.3, 35.7; HRMS (APCI) calcd for
C
15H12NO5, m/z¼286.0715
[(MþH)þ]; found, m/z¼286.0709; Chiralpak IA, n-hexane/2-
propanol¼4/1; flow rate 0.5 mL/min, 25 ꢀC, 215 nm, first peak:
tR¼34.3 min, second peak: tR¼46.1 min.
4.4. RC reaction of racemic 2 with catalyst (S)-16d
Compound 2c (R1¼iPr, R2¼R3¼H): 53% yield; white solid; mp
83e85 ꢀC; IR (KBr)
n
(cmꢁ1) 2950,1729,1667,1630,1402,1266,1190,
rac-2p: yellow oil; IR (KBr)
1190, 1048, 980, 889, 812; 1H NMR (CDCl3):
n
(cmꢁ1) 2986,1730,1642,1402,1273,
1096, 966, 902, 852; 1H NMR (CDCl3):
d
6.74 (d, J¼10.5 Hz, 2H), 6.34
d
6.88 (dd, J¼10.1,
(d, J¼17.4 Hz, 1H), 6.29 (d, J¼10.5 Hz, 2H), 6.05 (dd, J¼17.4, 10.5 Hz,
1H), 5.81 (d, J¼10.3 Hz, 1H), 2.17e2.08 (m, 1H), 0.93 (s, 3H), 0.92 (s,
3.2 Hz, 1H), 6.66 (m, 1H), 6.36 (dd, J¼17.6, 1.1 Hz, 1H), 6.21 (d,
J¼9.6 Hz, 1H), 6.06 (dd, J¼17.2, 10.3 Hz, 1H), 5.83 (dd, J¼10.1, 1.4 Hz,
3H); 13C NMR (CDCl3):
d
193.4, 167.1, 143.0, 136.2, 130.9, 123.7, 81.4,
1H), 1.88 (s, 3H), 1.56 (s, 3H); 13C NMR (CDCl3):
d 185.7, 164.6, 148.7,
47.1, 35.3; HRMS (APCI) calcd for
C
12H15O3, m/z¼207.1021
144.0, 134.9, 131.5, 128.1, 127.8, 74.8, 26.3, 15.6; HRMS (ESI) calcd for
[(MþH)þ]; found, m/z¼207.1012.
C
11H12NaO3, m/z¼215.0684 [(MþNa)þ]; found, m/z¼215.0674.
Compound 2l (R1¼3-NO2eC6H4, R2¼R3¼H): 68% yield; yellow
(S,S)-1p: 80% ee; [
a
]
ꢁ6.0 (c 0.1, CHCl3); yellow oil; IR (KBr)
n
22
D
solid; mp 80e83 ꢀC; IR (KBr)
n
(cmꢁ1) 3062, 1730, 1658, 1610, 1450,
(cmꢁ1) 2973, 1768, 1627, 1617, 1485, 1291, 1153, 1083, 980, 879; 1H
NMR (CDCl3):
6.36 (s, 1H), 6.27 (d, J¼3.2 Hz, 1H), 5.56 (J¼2.7 Hz,
1H), 3.33e3.28 (m, 1H), 2.89e2.77 (m, 2H), 1.76 (s, 3H), 1.70 (s, 3H);
13C NMR (CDCl3):
195.0, 168.6, 142.2, 137.8, 135.8, 122.3, 80.9, 45.2,
1383, 1123, 1091, 987, 880; 1H NMR (CDCl3):
d
8.39 (t, J¼2.1 Hz, 1H),
d
8.26e8.21 (m, 1H), 7.75e7.69 (m, 1H), 7.59 (t, J¼8.0 Hz, 1H), 6.99 (d,
J¼11.0 Hz, 2H), 6.53 (dd, J¼17.2, 1.1 Hz, 1H), 6.44 (d, J¼11.0 Hz, 2H),
6.27 (dd, J¼17.4, 10.5 Hz, 1H), 6.01 (dd, J¼10.3, 1.1 Hz, 1H); 13C NMR
d
36.2, 24.2, 15.6; HRMS (ESI) calcd for C11H12NaO3, m/z¼215.0684
[(MþNa)þ]; found, m/z¼215.0674; Chiralpak IC, n-hexane/2-
propanol¼4/1; flow rate 0.5 mL/min; 25 ꢀC; 215 nm, first peak:
tR¼18.1 min, second peak: tR¼22.6 min.
(CDCl3):
d 184.8, 163.9, 148.7, 145.9, 139.1, 133.1, 131.3, 130.2, 129.1,
127.5, 123.8, 120.6, 76.6; HRMS (ESI) calcd for HRMS (ACPI) calcd for
C
15H12NO5, m/z¼286.0715 [(MþH)þ]; found, m/z¼286.0709.
Compound 2m (R1¼R2¼Me, R3¼H): 59% yield; yellow solid; mp
(R)-2p: 80% ee; [
a
]
22 ꢁ41.6 (c 0.1, CHCl3); Chiralpak IC, n-hexane/
D
75e78 ꢀC; IR (KBr)
n
(cmꢁ1) 2945, 1783, 1649, 1453, 1335, 1267,
2-propanol¼4/1, flow rate 0.5 mL/min, 25 ꢀC, 215 nm, first peak:
tR¼13.9 min, second peak: tR¼25.7 min.
1098, 948, 889, 812; 1H NMR (CDCl3):
d
6.89 (d, J¼10.1 Hz, 2H), 6.25
(d, J¼10.1 Hz, 2H), 5.95e5.81 (m, 1H), 5.17 (d, J¼7.3 Hz, 1H), 3.10 (d,
rac-2q: yellow oil; IR (KBr) n
(cmꢁ1) 2989, 1730, 1668, 1627, 1401,
J¼6.9 Hz, 3H), 1.57 (s, 3H); 13C NMR (CDCl3):
d
185.1, 170.1, 149.0,
1285, 1191, 1053, 983, 880; 1H NMR (CDCl3):
d
6.85 (d, J¼10.1 Hz,
129.5, 128.1, 119.1, 74.4, 39.1, 26.1; HRMS (ESI) calcd for C11H12NaO3,
m/z¼215.0684 [(MþNa)þ]; found, m/z¼215.0674.
1H), 6.41 (dd, J¼17.1, 1.4 Hz, 1H), 6.22 (dd, J¼10.1, 1.8 Hz, 1H),
6.15e6.08 (m, 2H), 5.88 (dd, J¼10.3, 1.1 Hz, 1H), 1.91 (s, 3H), 1.53 (s,
Compound 2n (R1¼R3¼Me, R2¼H): 36% yield; white solid; mp
3H); 13C NMR (CDCl3):
d 185.5, 164.2, 159.1, 149.9, 132.2, 127.7, 127.5,
116e118 ꢀC; IR (KBr)
n
(cmꢁ1) 2991, 1732, 1628, 1410, 1299, 1191,
126.7, 76.3, 26.2, 17.7; HRMS (ESI) calcd for C11H12NaO3, m/
1138, 1060, 977, 888; 1H NMR (CDCl3):
J¼17.4, 1.4 Hz, 1H), 6.06 (dd, J¼17.4, 10.5 Hz, 1H), 5.82 (dd, J¼10.1,
1.4 Hz, 1H), 1.89 (s, 6H), 1.55 (s, 3H); 13C NMR (CDCl3):
186.4, 164.7,
d
6.67 (s, 2H), 6.36 (dd,
z¼215.0684 [(MþNa)þ]; found, m/z¼215.0674.
22
(S,S)-1q: 68% ee; [
a]
4.0 (c 0.1, CHCl3); yellow oil; IR (KBr) n
D
d
(cmꢁ1) 2917, 1716, 1614, 1629, 1456, 1280, 1271, 1053, 1025, 989; 1H
NMR (CDCl3):
6.27 (d, J¼3.2 Hz, 1H), 5.85 (s, 1H), 5.55 (d, J¼2.7 Hz,
1H), 3.37e3.31 (m, 1H), 2.87e2.75 (m, 2H), 2.02 (s, 3H), 1.75 (s, 3H);
13C NMR (CDCl3):
194.1, 168.3, 157.3, 137.2, 127.5, 121.9, 82.2, 46.1,
143.8, 134.5, 131.2, 128.4, 74.9, 26.4, 15.9; HRMS (APCI) calcd for
d
C
12H15O3, m/z¼207.1021 [(MþH)þ]; found, m/z¼207.1011.
d
4.3. General procedure for enantioselective RC reaction of 2
35.5, 22.7, 18.4; HRMS (ESI) calcd for C11H12NaO3, m/z¼215.0684
[(MþNa)þ]; found, m/z¼215.0674; Chiralpak IB, n-hexane/
ethanol¼19/1, flow rate 0.5 mL/min, 25 ꢀC, 215 nm, first peak:
A screw cap tube was charged with the catalyst (S)-16d
(0.05e0.08 mmol, 20e30 mol %) and the solution of dienone 2
(0.25 mmol) in CHCl3 (0.5 mL) at 0 ꢀC. The reaction mixture was
stirred until the reaction had reached completion by monitoring
with TLC analysis. After the purification via column chromatogra-
phy, the desired product 1 was obtained as colorless oil or white
solid.
tR¼38.9 min, second peak: tR¼41.2 min.
22
(R)-2q: 56% ee, [
a]
ꢁ140.8 (c 0.25, CHCl3); Chiralpak IC, n-
D
hexane/2-propanol¼4/1, flow rate 0.5 mL/min, 25 ꢀC, 215 nm, first
peak: tR¼48.7 min, second peak: tR¼54.2 min.
4.5. Synthetic transformations of (S,S)-1a
Compound 1c (R1¼iPr, R2¼R3¼H): 84% yield, 92% ee; white
solid; mp 81e84 ꢀC; [
a
]
22 ꢁ124.1 (c 0.25, CHCl3); IR (KBr)
n
(cmꢁ1
)
Compound 17: a solution of (S,S)-1a (26.7 mg, 0.150 mmol, 97%
ee) and Yb(OTf)3 (105.4 mg, 0.165 mmol) in MeOH (0.5 mL) was
stirred at room temperature for 15 min. And then NaBH4 (6.4 mg,
0.165 mmol) was added slowly at 0 ꢀC. The reaction was stirred for
15 min at 0 ꢀC, quenched with saturated aqueous solution of NH4Cl,
and then extracted with CH2Cl2, and dried over Na2SO4. The filtrate
was evaporated in vacuo. The residue was purified by silica gel
column chromatography (n-hexane/AcOEt¼2/1) to give the prod-
uct 17 (27.0 mg, 0.150 mmol, quant., 97% ee, dr 77:23). Minor di-
D
2971, 1763, 1679, 1398, 1356, 1248, 1160, 1138, 1110, 1049; 1H NMR
(CDCl3):
d
6.63 (dd, J¼10.5,1.8 Hz,1H), 6.33 (d, J¼3.2 Hz,1H), 6.11 (d,
J¼10.5 Hz, 1H), 5.60 (d, J¼3.2 Hz, 1H), 3.49e3.44 (m, 1H), 2.84 (d,
J¼5.0 Hz, 2H), 2.32e2.22 (m, 1H), 1.13 (t, J¼5.0 Hz, 6H); 13C NMR
(CDCl3): d 194.7, 145.2, 138.2, 130.6, 122.7, 84.7, 40.3, 37.6, 35.7, 17.4,
16.6; HRMS (APCI) calcd for C12H15O3, m/z¼207.1021 [(MþH)þ];
found, m/z¼207.1012; Chiralpak IC, n-hexane/2-propanol¼4/1, flow
rate 0.5 mL/min, 25 ꢀC, 215 nm, first peak: tR¼30.1 min, second
peak: tR¼32.5 min.
astereomer: 1H NMR (CDCl3):
d
6.30 (d, J¼3.2 Hz, 1H), 5.88 (d,
Compound 1l (R1¼3-NO2eC6H4, R2¼R3¼H): 82% yield, 88% ee;
J¼10.5 Hz, 1H), 5.73 (d, J¼10.5 Hz, 1H), 5.64 (d, J¼3.2 Hz, 1H),
22
yellow solid; mp 105e108 ꢀC; [
a
]
ꢁ18.6 (c 0.3, CHCl3); IR (KBr)
n
4.33e4.27 (m, 1H), 3.19e3.13 (m, 1H), 2.42e2.34 (m, 1H), 1.93e1.85
D
(cmꢁ1) 3021, 1750, 1684, 1589, 1325, 1268, 1154, 1164, 1098, 970,
(m, 1H), 1.59 (s, 3H); 13C NMR (CDCl3):
d 166.2, 138.3, 133.3, 130.6,

1208
S. Takizawa et al. / Tetrahedron 69 (2013) 1202e1209
Enantioselective Organocatalysis: Reactions and Experimental Procedures; Wiley-
VCH: Weinheim, 2007; (c) Pellissier, H. Tetrahedron 2007, 63, 9267; (d) Special
issue on organocatalysis (Ed.: List, B.)Chem. Rev. 2007, 107, 5413; (e) Marcia De
Figueiredo, R.; Christmann, M. Eur. J. Org. Chem. 2007, 2575; (f) Dondoni, A.;
Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638; (g) MacMillan, D. W. C. Nature
2008, 455, 304; (h) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178;
(i) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.; Jørgensen,
K. A. Chem. Commun. 2011, 632.
121.6, 81.1, 62.4, 43.6, 32.3, 26.2. Major diastereomer: colorless oil;
[
a
]
22 105.3 (c 0.1, CHCl3); IR (KBr)
n
(cmꢁ1) 3416, 2931, 1752, 1404,
6.21 (s,1H), 5.80
D
1284,1183,1130,1063, 929, 748; 1H NMR (CDCl3):
d
(d, J¼10.3 Hz, 1H), 5.65 (d, J¼10.3 Hz, 1H), 5.55 (s, 1H), 3.99e3.93
(m, 1H), 2.86e2.80 (m, 1H), 2.11e2.03 (m, 1H), 1.67e1.59 (m, 1H),
1.35 (s, 3H); 13C NMR (CDCl3):
d 169.3,138.2, 133.1, 130.6,121.4, 80.9,
2. (a) Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug Discovery Today
2007, 12, 8; (b) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed.
62.3, 43.4, 32.2, 26.0; Chiralpak IC, n-hexane/2-propanol¼4/1, flow
rate 0.5 mL/min, 25 ꢀC, 215 nm, first peak: tR¼21.6 min, second
peak: tR¼26.6 min; HRMS (ESI) calcd for C10H12NaO3, m/
z¼203.0684 [(MþNa)þ]; found, m/z¼203.0677; Chiralpak IC, n-
hexane/2-propanol¼4/1, flow rate 0.5 mL/min, 25 ꢀC, 215 nm, first
peak: tR¼11.9 min, second peak: tR¼13.1 min.
€
2007, 46, 1570; (c) Walji, A. M.; MacMillan, D. W. C. Synlett 2007, 1477; (d) Xu,
ꢀ~
L.-W.; Luo, J.; Lu, Y. Chem. Commun. 2009, 1807; (e) Nunez, M. G.; García, P.;
Moro, R. F.; Díez, D. Tetrahedron 2010, 66, 2089; (f) Grondal, C.; Jeanty, M.;
Enders, D. Nat. Chem. 2010, 2, 167; (g) Ishikawa, H.; Honma, M.; Hayashi, Y.
Angew. Chem., Int. Ed. 2011, 50, 2824.
3. Rauhut, M. M.; Currier, H. U.S. Patent 3,074,999; American Cyanamid, 1963.
4. For a short review on RC reaction, see Aroyan, C. E.; Dermenci, A.; Miller, S. J.
Tetrahedron 2009, 65, 4069.
Compound 18: to a solution of (S,S)-1a (26.7 mg, 0.150 mmol) in
0.3 mL CH2Cl2 at 0 ꢀC was added Br2 (8.2
mL, 0.158 mmol). The re-
5. For recent reviews and reports on MBH-type reaction, see: (a) Masson, G.;
Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 4614; (b) Ma, G.-N.; Jiang,
J.-J.; Shi, M.; Wei, Y. Chem. Commun. 2009, 5496; (c) Declerck, V.; Martinez, J.;
Lamaty, F. Chem. Rev. 2009, 109, 1; (d) Carrasco-Sanchez, V.; Simirgiotis, M. J.;
Santos, L. S. Molecules 2009, 14, 3989; (e) Basavaiah, D.; Reddy, B. S.; Badsara, S.
action was allowed to stir for 30 min at 0 ꢀC and then 0.1 mL of NEt3
was added and the reaction was warmed to room temperature. The
reaction mixture was concentrated in vacuo. The residue was pu-
rified by silica gel column chromatography (n-hexane/AcOEt¼2/1)
ꢀ
S. Chem. Rev. 2010, 110, 5447; (f) Mansilla, J.; Saa, J. M. Molecules 2010, 15, 709;
to give the product 18 (31.7 mg, 0.123 mmol, 82% yield, 97% ee).
(g) Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005; (h) Wang, S.-X.; Han, X.;
Zhong, F.; Wang, Y.; Lu, Y. Synlett 2011, 2766; (i) Zhong, F.; Han, X.; Wang, Y.; Lu,
Y. Angew. Chem., Int. Ed. 2011, 50, 7837; (j) Han, X.; Wan Zhong, F.; Lu, Y. J. Am.
Chem. Soc. 2011, 133, 1726; (k) Zhong, F.; Luo, J.; Chen, G.-Y.; Dou, X.; Lu, Y. J. Am.
Chem. Soc. 2012, 134, 10222; (l) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Chem. Sci.
2012, 3, 1231; (m) Han, X.; Zhong, F.; Wang, Y.; Lu, Y. Angew. Chem., Int. Ed. 2012,
51, 767.
6. (a) Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem.
Soc. 2002, 124, 2402; (b) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem.
Soc. 2002, 124, 2404; (c) Mergott, D. J.; Frank, S. A.; Roush, W. R. Org. Lett.
2002, 4, 3157; (d) Methot, J. L.; Roush, W. R. Org. Lett. 2003, 5, 4223; (e)
Winbush, S. M.; Mergott, D. J.; Roush, W. R. J. Org. Chem. 2008, 73, 1818; (f)
Seidel, F. O.; Gladysz, J. A. Adv. Synth. Catal. 2008, 350, 2443; (g) Yao, W.; Wu,
Y.; Wang, G.; Zhang, Y.; Ma, C. Angew. Chem., Int. Ed. 2009, 48, 9713; (h) Qiao,
Y.; Kumar, S.; Malachowski, W. P. Tetrahedron Lett. 2010, 51, 2636; (i) Liu, W.;
Zhou, J.; Zheng, C.; Chen, X.; Xiao, H.; Yang, Y.; Guo, Y.; Zhao, G. Tetrahedron
2011, 67, 1768; (j) Ma, J.; Xie, P.; Hu, C.; Huang, Y.; Chen, R. Chem.dEur. J. 2011,
17, 7418.
22
White solid; mp 144e146 ꢀC; [
a]
13.3 (c 0.41, CHCl3); IR (KBr) n
D
(cmꢁ1) 2925, 1767, 1688, 1435, 1389, 1253, 1182, 1067, 935, 821; 1H
NMR (CDCl3):
7.06 (s, 1H), 6.35 (d, J¼3.4 Hz, 1H), 5.62 (d, J¼3.4 Hz,
d
1H), 3.40e3.36 (m, 1H), 3.10 (dd, J¼12.6, 2.8 Hz, 1H), 2.95 (dd,
J¼12.6, 5.5 Hz, 1H), 1.77 (s, 3H); 13C NMR (CDCl3):
d 186.8, 167.8,
147.2, 136.7, 125.1, 123.4, 81.8, 45.2, 35.9, 23.9; Chiralpak IB, n-
hexane/ethanol¼19/1, flow rate 0.5 mL/min, 25 ꢀC, 250 nm, first
peak: tR¼47.9 min, second peak: tR¼51.7 min; HRMS (ESI) calcd for
C
10H9BrNaO3, m/z¼280.9612 [(MþNa)þ]; found, m/z¼280.9607.
Compound 19: A solution of dibenzyl malonate (48.6
mL,
0.198 mmol) and K2CO3 (49.8 mg, 0.360 mmol) in CH2Cl2 (0.18 mL)
at room temperature was stirred for 10 min, and then solution of
(S,S)-1a (32.1 mg, 0.180 mmol) and PPh3 (94.4 mg, 0.360 mmol) in
CH2Cl2 (0.18 mL) was added. The reaction was stirred for 6 h at
room temperature, quenched with saturated aqueous solution of
NH4Cl, extracted with AcOEt, and then dried over Na2SO4. The fil-
trate was evaporated in vacuo. The residue was purified by silica gel
column chromatography (n-hexane/AcOEt¼2/1) to give the prod-
7. (a) Aroyan, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 256; (b) Seidel, F.;
ꢀ
ꢀ
Gladysz, J. A. Synlett 2007, 986; (c) Marques-Lopez, E.; Herrera, R. P.; Marks, T.;
€
Jacobs, W. C.; Konning, D.; de Figueiredo, R. M.; Christmann, M. Org. Lett. 2009,
11, 4116; (d) Gong, J.-J.; Li, T.-Z.; Pan, K.; Wu, X.-Y. Chem. Commun. 2011, 1491; (e)
Aroyan, C. E.; Dermenci, A.; Miller, S. J. J. Org. Chem. 2010, 75, 5784; (f) Selig, P.
S.; Miller, S. J. Tetrahedron Lett. 2011, 52, 2148; (g) Dermenci, A.; Selig, P. S.;
Domaoal, R. A.; Spasov, K. A.; Anderson, K. S.; Miller, S. J. Chem. Sci. 2011, 2, 1568;
(h) Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988.
uct 19 (55.5 mg, 0.120 mmol, 67% yield, 97% ee, single di-
22
8. Wang, X.-F.; Peng, L.; An, J.; Li, C.; Yang, Q.-Q.; Lu, L.-Q.; Gu, F.-L.; Xiao, W.-J.
Chem.dEur. J. 2011, 17, 6484.
astereomer). Colorless oil; [
a
]
ꢁ40.9 (c 1.5, CHCl3); IR (KBr)
n
D
(cmꢁ1) 2952, 1767, 1740, 1687, 1453, 1380, 1214, 1155, 1096, 1036; 1H
NMR (CDCl3):
9. (a) Reynolds, T. E.; Binkley, M. S.; Scheidt, K. A. Org. Lett. 2008, 10, 2449; (b)
Zhao, Q.-Y.; Pei, C.-K.; Guan, X.-Y.; Shi, M. Adv. Synth. Catal. 2011, 353, 1973.
10. (a) Shi, Z.; Yu, P.; Loh, T.-P.; Zhong, G. Angew. Chem., Int. Ed. 2012, 51, 7825;
(b) Jin, Z.; Yang, R.; Du, Y.; Tiwari, B.; Ganguly, R.; Chi, Y. R. Org. Lett. 2012,
14, 3226.
11. (a) Schweizer, J.; Lattrell, R.; Hecker, E. Experientia 1975, 31, 1267; (b) Stern, A. J.;
Swenton, J. S. J. Org. Chem. 1988, 53, 2465; (c) McKinley, J.; Aponick, A.; Raber, J.
C.; Fritz, C.; Montgomery, D.; Wigal, C. T. J. Org. Chem. 1997, 62, 4874; (d) Su-
nasee, R.; Clive, D. L. J. Chem. Commun. 2010, 701; (e) Yakura, T.; Omoto, M.;
Yamauchi, Y.; Tian, Y.; Ozono, A. Tetrahedron 2010, 66, 5833.
d
7.33e7.25 (m, 10H), 6.59 (d, J¼10.5 Hz, 1H), 6.01 (d,
J¼10.5 Hz, 1H), 5.13 (s, 2H), 5.12 (s, 2H), 4.04 (dd, J¼6.0, 2.8 Hz, 1H),
2.63 (m, 2H), 2.49 (m, 2H), 2.21 (m, 2H), 1.61 (s, 3H); 13C NMR
(CDCl3): d 194.2, 175.4, 168.6, 168.4, 135.2, 129.2, 128.7, 128.5, 128.4,
80.0, 67.6, 48.8, 47.0, 42.0, 35.4, 27.5, 24.3; Chiralpak IB, n-hexane/
ethanol¼8/1, flow rate 0.5 mL/min, 25 ꢀC, 215 nm, first peak:
tR¼48.0 min, second peak: tR¼59.5 min; HRMS (ESI) calcd for
C
27H26NaO7, m/z¼485.1576 [(MþNa)þ]; found, m/z¼485.1576.
12. For recent reviews on the synthesis of a-methylidene-g-butyrolactones, see: (a)
Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew. Chem., Int. Ed. 2009, 48,
9426; (b) Ramachandran, P. V.; Yip-Schneider, M. T.; Schmidt, C. M. Future Med.
Chem. 2009, 1, 179.
Acknowledgements
13. (a) Rodriguez, E.; Towers, G. H. N.; Mitchell, J. C. Phytochemistry 1976, 15, 1573;
(b) Picman, A. K. Biochem. Syst. Ecol. 1986, 14, 255; (c) Ghantous, A.; Gali-
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14. (a) Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680; (b)
Matsui, K.; Takizawa, S.; Sasai, H. Synlett 2006, 761; (c) Matsui, K.; Tanaka, K.;
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kizawa, S.; Matsui, K.; Sasai, H. J. Synth. Org. Chem. Jpn. 2007, 65, 1089; (e) Ta-
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Kiriyama, K.; Ieki, K.; Sasai, H. Chem. Commun. 2011, 9227.
15. Takizawa, S.; Nguyen, T. M.-N.; Grossmann, A.; Enders, D.; Sasai, H. Angew.
Chem., Int. Ed. 2012, 51, 5423.
16. Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165.
17. (a) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125, 12094; (b)
McDougal, N. T.; Trevellini, W. L.; Rodgen, S. A.; Kliman, L. T.; Schaus, S. E. Adv.
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This work was supported by the CREST project of the Japan
Science and Technology Corporation (JST), Grant-in-Aid for Scien-
tific Research on Innovative Areas ‘Advanced Molecular Trans-
formations by Organocatalysts’ from The Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan. We thank
Deutsche Forschungsgemeinschaft (scholarship for A.G., In-
ternational Research Training Group ‘Selectivity in Chemo- and
Biocatalysis’dSeleCa, Germany). We acknowledge the technical
staff of the Comprehensive Analysis Center of ISIR, Osaka University
(Japan).
References and notes
18. (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc.
€
1. For selected reviews on organocatalysis, see: (a) Berkessel, A.; Groger, H.
1999, 121, 10219; (b) Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41, 4507; (c)
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S. Takizawa et al. / Tetrahedron 69 (2013) 1202e1209
Kawahara, S.; Nakano, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett.
1209
2003, 5, 3103; (d) Shi, M.; Chen, L.-H. Chem. Commun. 2003, 1310; (e) Shi, M.;
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19. In the absence of phenol, the reaction of 2a using 16b (20 mol %) gave the
product 1a in low yield (12%) with 60% ee.
20. Krauss, I. J.; Leighton, J. L. Org. Lett. 2003, 5, 3201.
21. The absolute configuration of 1 was assigned by comparison with an optical
rotation of the synthetic analog reported in the literature. See Ref. 11d.
22. This discrepancy in reactivity would be attributable to the ThorpeeIngold ef-
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27. Without using PPh3, 18 was formed with 57% yield in 78:22 dr. The high dia-
stereoselectivity (a single diastereomer was obtained) likely resulted from
a favorable SN2 reaction of intermediate IV.