Thiourea-catalyzed Morita-Baylis-Hillman reaction

Article abstract of DOI:10.1016/j.tet.2008.07.087

Here, we describe our studies on the thiourea-catalyzed Morita-Baylis-Hillman (MBH) reaction. Chemoselective activation of carbonyl compounds via hydrogen bonding to thiourea as a catalyst is the key to drastic rate acceleration of this reaction. The appl

Full text of DOI:10.1016/j.tet.2008.07.087

Tetrahedron 64 (2008) 9423–9429
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Thiourea-catalyzed Morita–Baylis–Hillman reaction
,
,
*
Yoshihiro Sohtome b y, Nobuko Takemura a, Rika Takagi a, Yuichi Hashimoto b, Kazuo Nagasawa a
a Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
b Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2008
Received in revised form 19 July 2008
Accepted 21 July 2008
Available online 26 July 2008
Here, we describe our studies on the thiourea-catalyzed Morita–Baylis–Hillman (MBH) reaction. Che-
moselective activation of carbonyl compounds via hydrogen bonding to thiourea as a catalyst is the key
to drastic rate acceleration of this reaction. The application of chiral bis-thiourea-type organocatalysts,
which can form a chiral double hydrogen-bonding network, is effective for enantioselective MBH re-
action. A cooperative system of bis-thiourea compounds, synthesized from 1,2-diaminocyclohexane, and
a Lewis base effectively promotes the MBH reaction at lower temperature, affording the MBH adducts in
33–95% yield with 44–90% ee. A plausible transition state model of the enantioselective MBH reaction is
presented.
Keywords:
Bis-thiourea
Organocatalyst
Morita–Baylis–Hillman
Enantioselective reaction
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
the reaction utilizing chiral catalysts is also of ongoing interest.16–19
The first catalytic highly enantioselective MBH reaction with
Asymmetric catalytic reactions are a central topic in modern
synthetic chemistry.1 Since we reported catalytic enantioselective
alkylation with chiral pentacyclic guanidine organocatalysts,2,3 in-
spired by biologically active natural products,4,5 we have continued
to explore chiral hydrogen-bonding donors as asymmetric orga-
nocatalysts.6–10 To promote the bond-forming process more effec-
tively by means of synergistic proximity,11 we have recently been
focusing on the design of chiral hydrogen-bonding networks con-
stituted from multiple hydrogen donors linked by a chiral spacer
(Fig. 1). The highly tunable properties of such catalysts with respect
to active sites, chiral spacer, and external bases have been utilized
by us facilitate various classes of catalytic asymmetric bond-form-
ing reactions.9 Here, we describe our studies on catalytic enantio-
selective Morita–Baylis–Hillman (MBH) reaction.
MBH reaction is a versatile carbon–carbon bond-forming re-
action for the synthesis of densely functionalized compounds from
aldehydes and electron-deficient alkenes in the presence of Lewis
bases such as tri-substituted phosphines and tertiary amines.12,13
Attracted by the complexity of the reaction sequences14 and the
great potential utility of the products as chiral building blocks,15
researchers have examined various approaches to make the re-
action more efficient. The development of an asymmetric version of
b-isocupredine (b-ICD) was reported by Hatakeyama’s group in
1999.16 Following their mechanistic proposals, enormous efforts
have been devoted to the exploration of asymmetric Lewis base
catalysts.17 Only two precedents utilizing chiral Brønsted acid/
Lewis base co-catalytic approaches had been reported by Ikegami’s
group18a and Schaus’ group18b before our strategy was developed.9b
Taking advantage of the ability of thiourea compounds to activate
carbonyl compounds,9a,20 we commenced a project to develop
thiourea-catalyzed MBH reaction as a new approach in this field.21
Herein, we describe (1) drastic rate acceleration of the MBH re-
action by thiourea compounds, (2) design and development of bis-
thiourea organocatalysts 1 (Fig. 2), leading to availability of the
enantioselective MBH reaction, and (3) a possible mechanism for
the rate enhancement and a plausible transition state model for
enantioselective MBH reaction.
Chiral spacer
Y
*
N
H
N
H
X
N
H
N
H
Nu
External
base
E
* Corresponding author.
Pre-Nu
Figure 1. Our concept for catalyst design.
E-mail address: knaga@cc.tuat.ac.jp (K. Nagasawa).
Present address: Department of Chemistry, Yale University, 225 Prospect Street,
PO Box 208107, New Haven, CT 06520, USA.
y
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.087

9424
Y. Sohtome et al. / Tetrahedron 64 (2008) 9423–9429
Table 1
MBH reaction using 2
R1
N
R2
N
S
N
S
N
CF3
CF3
H
H
Ar
Ar
2a: X = S
2b: X = O
X
H
H
1
F3C
O
N
H
N
H
CF3
Figure 2. The structure of bis-thiourea organocatalysts 1.
(0.2 eq)
O
OH
O
DABCO (0.25 eq)
No solvent, rt, 24 h
H
Y
Y
2. Results and discussion
n
n
3a
4: Y = O
5: Y = -CH2-
6: Y = O
2.1. Achiral diarylthiourea-catalyzed MBH reaction
7: Y = -CH2-
Since the MBH reaction is notoriously prone to be sluggish, se-
lection of a suitable catalyst core to activate reaction components
without decreasing the nucleophilicity of the Lewis base is partic-
ularly important. We previously reported that (thio)urea com-
Entry
Catalyst
Substrate
Product
Yielda (%)
O
1
2
3
None
2a
2b
6aa
6aa
6aa
26
62
58
O
O
pounds can enhance the aza-Michael reaction of a,b-unsaturated
carbonyl compounds with pyrrolidine.9a Based on those findings
we planned to apply the (thio)urea compounds to catalytic MBH
reaction via a tandem reaction sequence: aza-Michael, aldol, and
elimination.14 We hypothesized that if (thio)urea compounds could
chemoselectively activate both aldehydes and Michael acceptors
through double hydrogen-bonding interactions, the LUMO energy
of the carbonyl group should decrease in each step, thereby
resulting in rate acceleration of the reaction (Fig. 3).
4a
O
4
5
6
None
2a
2b
6ab
6ab
6ab
1
25
15
4b
O
7
8
9
None
2a
2b
7aa
7aa
7aa
1
60
52
We initially focused on the screening of suitable electrophiles in
the presence of diaza[2.2.2]bicyclooctane (DABCO) (25 mol %) un-
der solvent-free conditions.22 The results with Schreiner’s catalyst
2 (20 mol %)20e for the reaction of benzaldehyde (3a) with several
electrophiles are summarized in Table 1. As we expected, significant
rate enhancement was observed when both lactones 4 and cyclic
enones 5 were used as substrates (entries 1–12). Among the elec-
trophile investigated, cyclohexen-1-one (5a) gave promising re-
sults in terms of rate enhancement over the non-catalyzed reaction.
When we examined the MBH reaction of 3a with 5a, the product
was isolated in only 1% yield (entry 7). In contrast, addition of
biarylthiourea 2a gave the MBH adduct in 60% yield.23
To obtain structural insight into the catalytic activity of biar-
ylthiourea 2a, we performed experiments with structural variants
(Fig. 4). Removal of the trifluoromethyl groups on the aromatic
rings drastically decreased the reaction rate, suggesting the im-
portance of electron-withdrawing groups to increase the acidity for
catalytic activity. Since guanidinium salt 8 showed lower reactivity,
the thiourea functionality appeared to be more effective than the
corresponding guanidinium salt for carbonyl group activation.
These observations are consistent with findings for the aza-Michael
reaction,9a supporting the utility of a chemoselective carbonyl ac-
tivation strategy for catalytic MBH reaction.
5a
10
11
12
None
2a
2b
7ab
7ab
7ab
3
16
38
O
5b
a
Isolated yield.
NMR spectrum of a 1:1 mixture of 2a and each substrate showed
a downfield shift of N–H in 2a, confirming the carbonyl group ac-
tivation through hydrogen-bonding interaction between thiourea
2a and the substrates. These observations strongly suggest that
thiourea catalyst 2a would promote all the expected reaction se-
quences, i.e., (1) aza-Michael reaction, (2) aldol reaction, and (3)
elimination (Fig. 3).
2.2. Development of bis-thiourea organocatalyst for
enantioselective MBH reaction
We next attempted to extend our strategy to develop an enan-
tioselective variant of the reaction. Based on our proposed reaction
mechanism (Fig. 3), we postulated that if two active sites were
linked with a suitable chiral spacer, the carbon–carbon bond-
forming process would take place more effectively owing to
Crucial roles of hydrogen donors of 2a were indicated by the
results of 1H NMR studies with reaction components and the cor-
responding MBH product (Table 2). As shown in Table 2, the 1H
S
CF3
CF3
Ar
Ar
N
H
N
H
S
S
S
2a
F3C
S
N
H
N
H
CF3
CF3
Ar
O
Ar
2a
Ar
Ar
O
N
H
N
H
N
H
N
H
R1
H
2a
2a: 60% yield
CF3
Cl
O
C18H37
NH
O
H
O
OH
R1
X
X
Aldol reaction
R1
X
N
H
N
H
F3C
N
H
N
H
CF3
n
n
R3N
R3N+2a
R3N
n
2c: 20% yield
8: 11% yield
Elimination
Aza-Michael reaction
Figure 4. Reaction of 3a and 5a was conducted in the presence of 2a, 2c, and 8 under
Figure 3. Working model of 2a-catalyzed Morita–Baylis–Hillman reaction.
the same conditions as described in Table 1.

Y. Sohtome et al. / Tetrahedron 64 (2008) 9423–9429
9425
Table 2
Table 3
Effect of 3a, 5a, and 7aa on the 1H NMR signal of N–H in 2a
MBH reaction using bis-thioureas 1
O
O
OH
O
Entry
Substrate
N–H in 2a (ppm)
1 (0.2 eq)
DABCO (0.25 eq)
1
2
3
4
None
3a
5a
7.90
8.30
8.73
8.40
H
R
No solvent, rt, 24 h
7aa
3a
5a
7aa
Entry
Thiourea
Yielda (%)
eeb,c (%)
1
2
3
1a
1b
1c
1d
1d
72
51
47
20
46
33
11
5
proximity effects, and simultaneously, asymmetric induction might
be achieved. These speculations led us to prepare several types of
chiral catalysts 1 having two thiourea functionalities (Fig. 5). The
obvious advantages of the designed catalysts are facile synthesis
and potent stereochemical diversity.18e,f The bis-thiourea com-
pounds 1 can be easily prepared from isothiocyanate and chiral
diamine simply by mixing them in THF and recrystallizing the
product, without silica-gel column chromatography. With these
thiourea compounds 1 in hand, the coupling reaction of benzal-
dehyde (3a) and cyclohexen-1-one (5a) was examined under the
same conditions as described in Table 1 (Table 3).
4
d
5d
d
a
Isolated yield.
b
c
ee values were determined by HPLC using a chiral column.
Absolute stereochemistry of 7aa was determined by comparison of [a] value
D
with that reported by Schaus.18b
d
0.4 equiv of 1d was used.
CF3
S
N
H
N
H
CF3
Our investigation of the enantioselective MBH reaction revealed
that cyclohexanediamine was one of the most suitable chiral
spacers; 1a gave 7aa with 33% ee, favoring (R) configuration. It is
interesting to note that bis-thiourea 1a gave a greater rate-en-
hancing effect than biarylthiourea 2a (1a; 72% vs. 2a: 60%), al-
though the H-bonding ability of 1a, linked with a chiral spacer,
should be less than that of 2a. Compound 1b, having a flexible
chain-type chiral backbone, afforded the corresponding MBH
product in 51% yield with 11% ee (entry 2). The unsymmetric
thiourea 1c gave unsatisfactory results in terms of selectivity (entry
3; 47% yield, 5% ee). The existence of the hypothetical proximity
effect of two thiourea functionalities in 1a was supported by ex-
periments with the structural variant 1d (entries 4 and 5). Mono-
thiourea compound 1d had significantly lower catalytic activity
than 1a, even with a higher catalyst loading (entry 5).
In the bis-thiourea 1a-catalyzed MBH reaction, the Lewis base
had a great influence on enantioselectivity, as shown in Table 4.24
When we used phosphine, triazole, and triazine derivatives, almost
no reaction occurred (entries 1–5). In the case of imidazole, the
enantiomeric excess increased to 61% ee even at room temperature,
although the yield was low (entry 8). On the other hand, a co-
operative system of bis-thiourea 1a and DMAP resulted in a smooth
MBH reaction, giving 7aa in 90% yield, with 22% ee (entry 12).
Decreasing the temperature affected the reaction rate and slightly
improved the selectivity (entry 13). As shown in entry 14, addition
of MS4A was effective to increase the reactivity without loss of
enantioselectivity.
1d
Table 4
Enantioselective MBH reaction with various Lewis bases
O
O
OH
O
1a (0.2 eq)
Lewis base (0.25 eq)
No solvent, rt, 24 h
R
H
7ab
3a
5b
Entry
Lewis base
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
Ph3P
n-Bu3P
Trace
Trace
Trace
Trace
Trace
43
9
10
10
49
d
d
d
d
d
29
31
61
47
30
10
22
33
33
1H-1,2,4-Triazole
1H-1,2,3-Triazole
1,3,5-Triazine
1-Metylpyrrolidine
1,4-Dimethylpiperazine
Imidazole
9
N-Methylimidazole
Et3N
10
11
12
13c
14c,d
i-Pr2NEt
DMAP
DMAP
DMAP
6
90
25
45
a
Isolated yield.
b
c
ee values were determined by HPLC using chiral column.
ꢀ10 ꢁC.
d
MS4A was added.
Encouraged by these preliminary results, we examined the
scope of substrates with the cooperative system of C2 symmetric
chiral thiourea compound 1a and Lewis base (Table 5). We exam-
ined the feasibility of enantioselective MBH reaction of various al-
dehydes 3 with cyclic enones 5 by using 0.4 equiv of 1a and Lewis
base, respectively. In this system, high reactivity was consistently
obtained when aromatic (entries 1–4) or aliphatic aldehydes in-
cluding linear (entries 5–7), branched (entries 8–10) and cyclic
compounds (entries 11–14) were used as electrophiles. As shown in
entries 1 and 3, the cooperative procedure with 1a and DMAP
smoothly enhanced the MBH reaction of aromatic aldehydes to give
the corresponding MBH adducts even at subzero temperature with
moderate ee (entry 1; 42% ee, entry 3; 33% ee). The use of imidazole
instead of DMAP significantly improved the selectivity, giving the
corresponding MBH products with 44–57% ee, although the re-
activity was decreased (entries 2 and 4). In these bis-thiourea/
Bn
N
Ph
Ph
N
S
N
S
N
S
N
S
N
S
N
S
N
N
N
N
N
H
H
1c
H
H
1b
H
H
1a
Ar
Ar
Ar
Ar
Ar
Ar
H
H
H
H
H
H
Ar = 3,5-(CF3)2-C6H3-
Figure 5. Structures of bis-thioureas 1a, 1b, and 1c.

9426
Y. Sohtome et al. / Tetrahedron 64 (2008) 9423–9429
Table 5
8–10). When this system was applied to cyclic aldehydes, the ee
Enantioselective MBH reaction with 1a
values reached up to 90% ee (entries 11–14). Thus, we have de-
veloped new enantioselective MBH reaction with a bis-thiourea/
Lewis base co-catalytic system. Further improvement of the cata-
lytic efficiency is under investigation.
O
OH
O
1a (0.4 eq)
O
DMAP (0.4 eq)
R1
+
R1
H
R
MS4A
no solvent
5a: nn= 1
5b: n = 0
(2.0 equiv)
n
3
7
2.3. Hypothetical transition state model
The origin of stereodiscrimination was examined by 1H NMR
analysis. As shown in Figure 6, complexation with (R,R)-1a and (R)-
7ga (60% ee) caused significant splitting of the isopropyl signals of
7ga. The observation that only the matched (R)-product showed
a downfield shift with (R,R)-catalyst suggests the existence of in-
teraction between the newly generated secondary alcohol moiety
in (R)-7ga and thiourea functionality in (R,R)-1a (III in Scheme 1).
Our hypothetical dual activation mode in the transition state can
explain the results and the stereodiscrimination process. In the
mechanism outlined in Scheme 1, two thiourea functionalities co-
ordinate to the carbonyl groups of the aldehyde and enolate, re-
spectively.25 Substituent (R1) in the aldehyde favors an anti
relationship to avoid disrupting the hydrogen-bonding interaction
between thiourea and enolate. We considered that carbonyl group
activation by a thiourea functionality in II leads to rapid and irre-
versible elimination of tertiary amine, which is currently consid-
ered to be the rate-determining step,14 to generate complex III.
Thus, (R)-7 should be produced as the major product. This model is
consistent with previously proposed transition states in guanidi-
nium/thiourea-catalyzed asymmetric nitroaldol reactions de-
veloped by our group.9c–g
Entry
Aldehyde
Enone Temp (ꢁC) Time (h) Product Yielda (%) eeb,c (%)
O
1
5a
5a
ꢀ10
48
120
7aa
7aa
88
40
42
57
H
2d
rt
3a
O
H
3
5a
5a
ꢀ5
72
120
7ba
7ba
99
95
33
44
4d
4
F3C
3b
O
5
5a
ꢀ5
72
7ea
33
59
Ph
H
3e
O
6
7
5a
5b
ꢀ5
72
48
7fa
7fb
63
50
60
56
Me
H
ꢀ20
5
3f
O
Me
Et
H
8
5a
ꢀ5
72
7ga
67
60
3. Conclusions
Me
3g
We have developed a new approach to the MBH reaction uti-
lizing a cooperative system of thiourea catalyst and Lewis base.
First, basic methodology for the MBH reaction using achiral biaryl-
thiourea was explored, and drastic rate acceleration was achieved.
Second, based on mechanistic studies of the racemic version of the
reaction, we developed novel bis-thiourea-type organocatalysts,
which permit enantioselective MBH reaction. These two-center
organocatalysts can be classified as homo-bifunctional organo-
catalysts in our proposed catalyst framework. Third, NMR studies
yielded several mechanistic insights, and we propose a plausible
transition state for thiourea-catalyzed MBH reaction. Precise
mechanistic studies aimed at improving the catalyst efficiency in
the enantioselective version of this reaction are ongoing. Further
efforts to apply our concept to other classes of asymmetric C–C
bond-forming reaction are also in progress.
O
9
10
5a
5b
ꢀ5
72
72
7ha
7hb
53
55
72
70
H
ꢀ40
Et
3h
O
O
11
12
5a
5b
ꢀ5
72
48
7ia
7ib
55
62
86
75
H
H
ꢀ40
3i
13
14
5a
5b
ꢀ5
72
48
7ja
7jb
72
71
90
85
ꢀ40
3j
Isolated yield.
a
b
c
ee values was determined by HPLC using a chiral column.
4. Experimental
4.1. General
Absolute stereochemistry of new products was determined by Sharpless epox-
idation method.18b
d
0.4 equiv of imidazole was used as Lewis base.
Flash chromatography was performed using Silica gel 60
(spherical, particle size 0.040–0.100 mm; Kanto Co., Inc., Japan).
Optical rotations were measured with a JASCO DIP polarimeter 370.
IR spectra were measured with JASCO VALOR-III FT-IR spectro-
photometer. 1H and 13C NMR spectra were recorded on JEOL JNM-
AL300 or JEOL JMN-EX400 or JEOL ALPHA500 instrument. Mass
spectra were recorded on JEOL JMA-HX110 spectrometer.
imidazole co-catalyzed reactions of aromatic aldehydes, the C–C
bond-forming process might take place predominantly through
expected dual activation mode. It is noteworthy that aliphatic al-
dehydes having an enolizable carbonyl group gave only MBH ad-
ducts without generating self-aldol products (entries 5–14). Linear
aldehydes afforded the MBH products with 59–60% ee (entries 5
and 6). In the present system, the five-membered enone 5b was
more reactive than 5a, and the reaction was performed at ꢀ20 ꢁC to
give 7fb with 56% ee. The ee values increased as the bulk at the
4.2. Typical procedure for synthesis of bis-thiourea 1
To a solution of (1R,2R)-(–)-1,2-diaminocyclohexane (866 mg,
7.58 mmol) in THF (10 mL) was added 3,5-bis(trifluoro-
methyl)phenyl isothiocyanate (2.77 mL, 15.2 mmol) at 0 ꢁC, and
the mixture was stirred for 10 min. After warming to room
a
a
-position of the carbonyl group in 3 was increased (entries 8–14).
-Substituted aldehydes gave the products with 60–72% ee (entries

Y. Sohtome et al. / Tetrahedron 64 (2008) 9423–9429
9427
(a)
(b)
OH
O
OH O
S
S
N
Me
Me
N
H
N
H
Me
7ga (60% ee)
Me
7ga (60% ee)
Ar
N
Ar
H
H
1a
Figure 6. 1H NMR spectra (CDCl3) showing the methyl signals of 7ga. (a) without 1a. (b) 7ga: 1a¼1:1 mixture.
temperature, the reaction mixture was stirred for 22 h and con-
centrated in vacuo. The residue was recrystallized from ethyl ace-
tate–hexane to give 1a (4.68 g, 94%) as a white solid.
(125 MHz, CD3OD) d 183.5, 182.9, 142.8, 142.7, 138.9, 132.7
(JCF¼33.1 Hz), 130.3, 129.6, 127.7, 124.7 (JCF¼273.1 Hz), 124.0 (br),
118.11, 57.0, 39.3. HRMS (FAB, MþH) calcd for C27H21F12N4S2
693.1016, found 693.1014.
4.2.1. Bis-thiourea 1a
25
Mp¼132–133 ꢁC (decomposition). [
a]
ꢀ60.6 (c 1.0, CHCl3). IR
D
4.3. Typical procedure for enantioselective Baylis–Hillman
reaction
(KBr) 3357, 3280, 3065, 2950, 1688, 1573, 1473, 1389, 1279, 1189,
1124 cmꢀ1. 1H NMR (500 MHz, CDCl3)
7.69 (s, 2H), 7.07 (br s, 2H), 4.38 (br s, 2H), 2.20 (br s, 2H), 1.81 (br s,
2H), 1.35 (br s, 4H). 13C NMR (125 MHz, CDCl3)
180.5, 138.6, 132.8
d 8.12 (br s, 2H), 7.81 (s, 4H),
To a mixture of 2-cyclohexene-1-one (5a) (150 mL, 1.60 mmol),
d
bis-thiourea catalyst 1a (210 mg, 0.320 mmol), DMAP (39.1 mg,
0.320 mmol), and MS4A was added cyclohexanecarboxaldehyde
(JCF¼33.1 Hz), 124.1 (br), 122.7 (JCF¼273.1 Hz), 119.7 (br), 59.5, 31.7,
24.4. HRMS (FAB, MþH) calcd for C24H21F12N4S2 657.1016, found
657.1031.
(3j) (97.0
m
L, 0.800 mmol) at ꢀ5 ꢁC. The resulting mixture was
stirred vigorously at ꢀ5 ꢁC for 72 h. Then saturated NH4Claq was
added, and the organic layer was extracted with ethyl acetate. The
extracts were dried over MgSO4, filtered and concentrated in vacuo,
and the residue was purified by column chromatography on silica
gel (hexane/ethyl acetate¼8/1, 2/1) to give 7ja (119 mg, 72%). The
enantiomeric excess of 7ja (90% ee) was determined by the use of
4.2.2. Bis-thiourea 1b
25
White solid. Mp¼185–186 ꢁC (decomposition). [
a]
ꢀ57.4 (c 1.0,
D
CHCl3). IR (KBr) 3300, 3111, 2940, 2864, 1644, 1582, 1471, 1446,
1388, 1283, 1230, 1181, 1130 cmꢀ1. 1H NMR (500 MHz, CDCl3)
(br s, 2H), 7.72 (s, 4H), 7.70 (s, 2H), 7.51 (br s, 2H), 7.25–7.16 (m,10H),
6.01 (br s, 2H). 13C NMR (125 MHz, CDCl3)
180.6,138.4,136.8,133.0
d 8.07
chiral HPLC analysis. (Chiralcel OB-H, 0.46 cm (
4
)ꢂ25 cm (L),
d
n-hexane/2-propanol¼99/1, 1.0 mL/min, (R) major; 13.5 min, (S)
24
(JCF¼33.1 Hz), 129.1, 128.7, 127.6, 124.0 (br), 122.6 (JCF¼273.1 Hz),
minor; 14.7 min). [
a
]
D
þ50.2 (c 1.03, CHCl3). Characterization and
spectroscopic data were in agreement with literature.18b
119.8 (br), 64.9. HRMS (FAB, MþH) calcd for
C32H23F12N4S2
755.1173, found 755.1174.
4.3.1. 7ba (Table 5, entry 3)
23
4.2.3. Bis-thiourea 1c
Colorless oil. [
a
]
ꢀ1.4 (c 0.80, benzene, 33% ee). IR (neat) 3424,
D
25
2952, 1666, 1415, 1376, 1326, 1258, 1164, 1121, 1067, 1017 cmꢀ1. 1H
NMR (500 MHz, CDCl3)
[
a]
ꢀ30.4 (c 1.5, CD3OD). IR (neat) 3231, 1543, 1471, 1381, 1278,
D
1175, 1133 cmꢀ1. 1H NMR (500 MHz, CDCl3)
d 8.12 (s, 2H), 8.06 (s,
d
7.59 (d, J¼8.1 Hz, 2H), 7.48 (d, J¼8.1 Hz,
2H), 7.59 (s, 1H), 7.58 (s, 1H), 7.34–7.21 (m, 5H), 5.13 (br s, 1H), 4.06
2H), 6.77 (t, J¼4.1 Hz, 1H), 5.58 (d, J¼4.7 Hz, 1H), 3.54 (d, J¼5.6 Hz,
(br s, 1H), 3.73 (br d, J¼11.9 Hz, 1H), 3.30 (br, 2H). 13C NMR
1H), 2.47–2.39 (m, 4H), 2.00 (m, 2H). 13C NMR (125 MHz, CDCl3)
S
S
S
S
N
H
S
S
N
H
N
H
N
N
N
N
Ar
(R)-7
(R,R)-1a
Ar
N
Ar
N
H
H
O
H
O
N
H
N
H
N
Ar
H
H
Ar
Ar
O
O
H
R3N
Fast
H
O
H
O
R1
H
R1
H
NR3
H
NR3
R1
I
II
III
(Observed by 1H NMR)
Scheme 1. Plausible transition state of (R,R)-1a-catalyzed MBH reaction.

9428
Y. Sohtome et al. / Tetrahedron 64 (2008) 9423–9429
d
200.3, 145.8, 140.5, 126.7 (br), 125.2 (JCF¼4.1 Hz), 122.0
(JCF¼271.0 Hz), 72.2, 38.5, 25.7, 21.4. HRMS (FAB, MþH) calcd for
14H14F3O2 271.0946, found 271.0970. HPLC (Chiralcel OB-H,
0.46 cm (
(125 MHz, CDCl3) d 210.4, 158.7, 147.1, 71.7, 44.6, 35.2, 29.2, 28.6,
26.7, 25.6, 25.6. HRMS (FAB, MþNa) calcd for C11H16O2Na 203.1048,
C
found 203.1049. HPLC (Chiralcel OD-H, 0.46 cm (
4
)ꢂ25 cm (L),
4
)ꢂ25 cm (L), n-hexane/2-propanol¼75/5, 0.8 mL/min, (S)
n-hexane/2-propanol¼98/2, 0.8 mL/min, (R) major; 7.5 min, (S)
minor; 13.1 min, (R) major;14.8 min).
minor; 8.5 min).
4.3.2. 7fa (Table 5, entry 6)
4.3.8. 7jb (Table 5, entry 14)
23
28
Colorless oil. [
a
]
D
þ17.6 (c 0.87, CHCl3, 60% ee). IR (neat) 3430,
Colorless oil. [
a]
þ30.6 (c 1.09, CHCl3, 85% ee). IR (neat) 3434,
D
2925, 2857, 1668, 1456, 1380, 1278, 1172, 1136 cmꢀ1
.
1H NMR
2925, 2852, 1695, 1448, 1259, 1101 cmꢀ1. 1H NMR (500 MHz, CDCl3)
(500 MHz, CDCl3)
d
6.86 (t, J¼4.3 Hz, 1H), 4.27 (br, 1H), 2.87 (br s,
d
7.41 (t, J¼2.4 Hz, 1H), 4.18 (d, J¼6.4 Hz, 1H), 2.80–2.62 (m, 2H),
1H), 2.45–2.38 (m, 4H), 2.00 (m, 2H), 1.61 (m, 2H), 1.40–1.25 (m,
2.45–2.44 (m, 2H), 1.83 (d, J¼12.8 Hz, 1H), 1.76–1.70 (m, 2H), 1.66–
8H), 0.87 (t, J¼6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3)
d 200.7, 145.7,
1.57 (m, 2H), 1.52 (d, J¼12.8 Hz, 1H), 1.25–0.95 (m, 5H). 13C NMR
140.9, 71.8, 38.7, 36.2, 31.8, 29.1, 26.0, 25.7, 22.6 (br), 14.1. HRMS
(125 MHz, CDCl3) d 210.2, 159.2, 146.2, 73.1, 42.6, 35.3, 29.5, 27.9,
(FAB, MþH) calcd for C13H23O2 211.1698, found 211.1731. HPLC
26.7, 26.3, 26.0, 25.9. HRMS (FAB, MþNa) calcd for C12H18O2Na
(Chiralcel OD-H, 0.46 cm (
4
)ꢂ25 cm (L), n-hexane/2-propanol¼99/
217.1204, found 217.1242. HPLC (Chiralcel OB-H, 0.46 cm (
4
)ꢂ25 cm
1, 1.0 mL/min, (R) major; 18.3 min, (S) minor; 22.6 min).
(L), n-hexane/2-propanol¼99.7/0.03, 1.0 mL/min, (R) major;
41.5 min, (S) minor; 47.2 min).
4.3.3. 7fb (Table 5, entry 7)
25
Colorless oil. [
a
]
þ3.1 (c 0.98, CHCl3, 55% ee). IR (neat) 3274,
Acknowledgements
D
2927, 2856, 1691, 1629, 1520, 1366, 1279, 1173, 1137 cmꢀ1. 1H NMR
(500 MHz, CDCl3)
d
7.44 (br s, 1H), 4.43 (t, J¼6.4 Hz, 1H), 2.62–2.61
Y.S. gratefully acknowledges a JSPS Postdoctoral Fellowship for
Research Abroad. This research was supported in part by grants
from Mitubishi Chemical Corporation, the Uehara Memorial
Foundation, and the Nagase Science and Technology Foundation.
(m, 2H), 2.45–2.43 (m, 2H), 1.69–1.64 (m, 2H), 1.47–1.42 (m, 1H),
1.33–1.25 (m, 7H), 0.87 (t, J¼6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3)
d
210.1, 157.8, 147.8, 67.9, 35.8, 35.2, 31.8, 29.1, 26.6, 25.4, 22.6, 14.1.
HRMS (FAB, MþH) calcd for C12H21O2 197.1542, found 197.1537.
HPLC (Chiralcel OD-H, 0.46 cm (
4)ꢂ25 cm (L), n-hexane/2-prop-
References and notes
anol¼98/2, 1.0 mL/min, (R) major; 30.9 min, (S) minor; 38.2 min).
1. For a general review, see: Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, NY, 2004.
2. For recent reviews of chiral guanidine catalysts, see: (a) Ishikawa, T.; Kuma-
moto, T. Synthesis 2006, 737; (b) Ishikawa, T.; Isobe, T. Chem.dEur. J. 2002,
8, 552.
3. For our work utilizing chiral pentacyclic guanidine catalysts, see: (a) Nagasawa,
K.; Georgieva, A.; Takahashi, H.; Nakata, T. Tetrahedron 2000, 56, 187; (b) Na-
gasawa, K.; Georgieva, A.; Takahashi, H.; Nakata, T. Tetrahedron 2001, 57, 8959;
(c) Kita, T.; Georgieva, A.; Hashimoto, Y.; Nakata, T.; Nagasawa, K. Angew. Chem.,
Int. Ed. 2002, 41, 2832.
4.3.4. 7ha (Table 5, entry 9)
25
Colorless oil. [
a]
þ5.9 (c 0.31, CHCl3, 72% ee). IR (neat) 3447,
D
2959, 2873, 1667, 1459, 1378, 1172, 1138 cmꢀ1. 1H NMR (500 MHz,
CDCl3)
6.83 (t, J¼4.0 Hz, 1H), 4.12 (d, J¼6.7 Hz, 1H), 2.45–2.40 (m,
2H), 2.04–1.95 (m, 2H), 1.59–1.52 (m, 4H), 1.42–1.35 (m, 1H), 1.25–
1.17 (m, 2H), 0.88–0.84 (m, 6H). 13C NMR (125 MHz, CDCl3)
200.8,
d
d
146.9, 139.8, 74.6, 44.8, 38.9, 25.8, 22.5, 22.3, 20.4, 10.9, 10.6. HRMS
4. For a general review, see: Berlinck, R. G. S.; Kossuga, M. H. Nat. Prod. Rep. 2005,
22, 516.
(FAB, MþH) calcd for C12H21O2 197.1542, found 197.1508. HPLC
(Chiralcel OD-H, 0.46 cm (
0.8 mL/min, (R) major; 6.7 min, (S) minor; 7.7 min).
4
)ꢂ25 cm (L), n-hexane/ethanol¼98/2,
5. For our work, see: (a) Nagasawa, K.; Georgieva, A.; Koshino, H.; Nakata, T.; Kita,
T.; Hashimoto, Y. Org. Lett. 2002, 4, 177; (b) Ishiwata, T.; Hino, T.; Koshino, H.;
Hashimoto, Y.; Nakata, T.; Nagasawa, K. Org. Lett. 2002, 4, 2921; (c) Nagasawa,
K.; Hashimoto, Y. Chem. Rec. 2003, 3, 201; (d) Shimokawa, J.; Shirai, K.; Tanatani,
A.; Hashimoto, Y.; Nagasawa, K. Angew. Chem., Int. Ed. 2004, 43, 1559; (e) Shi-
mokawa, J.; Ishiwata, T.; Shirai, K.; Koshino, H.; Tanatani, A.; Nakata, T.;
Hashimoto, Y.; Nagasawa, K. Chem.dEur. J. 2005, 11, 6878; (f) Nagasawa, K.;
Shimokawa, J. J. Synth. Org. Chem. Jpn. 2006, 64, 539; (g) Shimokawa, J.; Iijima,
Y.; Hashimoto, Y.; Chiba, H.; Tanaka, H.; Nagasawa, K. Heterocycles 2007, 72, 145;
(h) Iwamoto, O.; Koshino, H.; Hashizume, D.; Nagasawa, K. Angew. Chem., Int.
Ed. 2007, 46, 8625.
6. For reviews concerning asymmetric catalysis by hydrogen-bonding donors,
see: (a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713; (b) Takemoto, Y.;
Miyabe, H. Chimia 2007, 61, 269; (c) Connon, S. J. Chem.dEur. J. 2006, 12, 5418;
(d) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520; (e)
Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999; (f) Takemoto,
Y. Org. Biomol. Chem. 2005, 3, 4299; (g) Schreiner, P. R. Chem. Soc. Rev. 2003, 32,
289.
4.3.5. 7hb (Table 5, entry 10)
25
Colorless oil. [
a
]
þ32.5 (c 1.01, CHCl3, 70% ee). IR (neat) 3438,
D
2962, 2931, 2875, 1694, 1464, 1382, 1279, 1179, 1136 cmꢀ1. 1H NMR
(500 MHz, CDCl3)
7.44–7.43 (m, 1H), 4.44 (d, J¼5.8 Hz, 1H), 2.64–
d
2.62 (m, 2H), 1.57–1.25 (m, 5H), 0.90 (t, J¼7.5 Hz, 3H), 0.88 (t,
J¼7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3)
d 210.3, 159.0, 146.7, 70.0,
45.2, 35.3, 26.6, 22.1, 20.6, 11.4, 11.2. HRMS (FAB, MþNa) calcd for
C
11H18O2 Na 205.1204, found 205.1234. HPLC (Chiralcel OD-H,
0.46 cm (
4
)ꢂ25 cm (L), n-hexane/2-propanol¼98/2, 1.0 mL/min, (R)
major; 14.9 min, (S) minor; 17.8 min).
7. For pioneering work utilizing urea/thiourea catalysts by Jacobsen’s group, see:
(a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901; (b) Vachal, P.;
Jacobsen, E. N. Org. Lett. 2000, 2, 867; (c) Sigman, M. S.; Vachal, P.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2000, 39, 1279; (d) Vachal, P.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 10012; (e) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 12964; (f) Wenzel, A. G.; Jacobsen, E. N. Synlett 2003, 1919; (g) Joly,
G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102; (h) Taylor, M. S.; Jacobsen,
E. N. J. Am. Chem. Soc. 2004, 126, 10558; (i) Fuerst, D. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2005, 127, 8964; (j) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2005, 44, 466; (k) Raheem, I. T.; Jacobsen, E. N. Adv. Synth. Catal. 2005, 347, 1701;
(l) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170; (m) Lalonde, M. P.;
Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366; (n) Tan, K. L.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46, 1315; (o) Raheem, I. T.; Thiara, P. S.;
Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404; (p) Zuend, S. J.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 15872; (q) Raheem, I. T.; Thiara, P. S.;
Jacobsen, E. N. Org. Lett. 2008, 10, 1577; (r) Fang, Y.-Q.; Jacobsen, E. N. J. Am. Chem.
Soc. 2008, 130, 5660.
4.3.6. 7ia (Table 5, entry 11)
23
Colorless oil. [
a
]
þ38.2 (c 0.96, CHCl3, 85% ee). IR (neat) 3438,
D
2950, 2867, 1666, 1381, 1258, 1172, 1027 cmꢀ1. 1H NMR (500 MHz,
CDCl3)
6.83 (t, J¼4.1 Hz, 1H), 3.94 (d, J¼9.0 Hz, 1H), 2.44–2.38 (m,
4H), 2.19 (m, 1H), 1.97 (m, 2H), 1.82 (m, 1H), 1.62–1.42 (m, 6H), 1.07
(m, 1H). 13C NMR (125 MHz, CDCl3)
200.93, 146.61, 140.30, 76.97,
d
d
44.99, 38.78, 29.93, 29.44, 25.72, 25.46 (br), 22.53. HRMS (FAB,
MþH) calcd for C12H19O2 195.1385, found 195.1397. HPLC (Chiralcel
OB-H, 0.46 cm (
min, (R) major; 17.6 min, (S) minor; 19.8 min).
4
)ꢂ25 cm (L), n-hexane/2-propanol¼99/1, 1.0 mL/
4.3.7. 7ib (Table 5, entry 12)
25
Colorless oil. [
a
]
D
þ32.4 (c 1.08, CHCl3, 75% ee). IR (neat) 3439,
2952, 2868, 1695, 1441, 1374, 1344, 1196 cmꢀ1. 1H NMR (500 MHz,
8. For work by Takemoto’s group utilizing bifunctional urea/thiourea catalysts,
see: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672; (b)
Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625; (c)
Hoashi, Y.; Yabuta, T.; Takemoto, T. Tetrahedron Lett. 2004, 45, 9185; (d) Okino,
CDCl3)
d
7.45 (t, J¼2.3 Hz, 1H), 4.22 (d, J¼7.9 Hz, 1H), 2.62 (br d,
J¼4.0 Hz, 2H), 2.45–2.43 (m, 2H), 1.80–1.18 (m, 8H). 13C NMR

Y. Sohtome et al. / Tetrahedron 64 (2008) 9423–9429
9429
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Li, B.-J.; Lin, J.; Liu, M.; Chen, Y.-C.; Ding, Li.-S.; Wu, Y. Synlett 2005, 603; (g)
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ama, M. Tetrahedron: Asymmetry 1995, 6, 1241; (b) Marko, I. E.; Giles, P. R.;
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S. J. Tetrahedron 2006, 62, 11450; (f) Aroyan, C. E.; Vasbinder, M. M.; Miller, S. J.
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and references cited therein.
18. For chiral Brønsted acid and achiral Lewis base system, see: Ref. 9b as well
as (a) Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165; (b)
McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125, 12094; (c)
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Adv. Synth. Catal. 2004, 346, 1231; (d) Rodgen, S. A.; Schaus, S. E. Angew.
Chem., Int. Ed. 2006, 45, 4929; Recently improved bis-thiourea catalysts were
reported by Berkessel’s group and Shi’s group; (e) Berkessel, A.; Roland, K.;
Neudo¨fl, J. M. Org. Lett. 2006, 8, 4195; (f) Shi, M.; Liu, X.-G. Org. Lett. 2008,
10, 1043.
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Biomol. Chem. 2007, 5, 2027; (b) Shibasaki, M.; Kanai, M.; Matsunaga, S.
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5247; (i) Rowlands, G. J. Tetrahedron 2001, 57, 1865.
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12. (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815; (b)
Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, 1972; Chem. Abstr. 1972,
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21. Portions of this work were reported previously as a communication; see Ref. 9b.
22. For
a recent review of solvent-free approaches, see: Walsh, P. J.; Li, H.;
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23. These results are not entirely novel; Connon and Maher also reported very
similar results with the use of methyl acrylate and methyl vinyl ketone,20k at
almost the same time as our report.9b
24. Since the ee values were independent of time-course, the stereochemistry of
the MBH product was concluded to be kinetically controlled.
25. Jones, C. E. S.; Turega, S. M.; Clarke, M. L.; Philp, D. Tetrahedron Lett. 2008, 49,
4666.