Highly Enantioselective Intramolecular Morita-Baylis-Hillman Reaction Catalyzed by Mannose-Based Thiourea-phosphine

Article abstract of DOI:10.1002/cjoc.201500468

The saccharide-based chiral bifunctional thiourea-phosphines were developed as chiral organocatalysts for the intramolecular Morita-Baylis-Hillman reaction of ω-formyl-enones. With only 2 mol% of thiourea-phosphine catalyst 3c, chiral functionalized cyclo

Full text of DOI:10.1002/cjoc.201500468

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DOI: 10.1002/cjoc.201500468
Highly Enantioselective Intramolecular Morita-Baylis-Hillman
Reaction Catalyzed by Mannose-Based Thiourea-phosphine
Weihong Yang, Kui Yuan, Hongliang Song, Feng Sha, and Xinyan Wu*
Key Laboratory for Advanced Material and Institute of Fine Chemicals, East China University of Science and
Technology, Shanghai 200237, China
The saccharide-based chiral bifunctional thiourea-phosphines were developed as chiral organocatalysts for the
intramolecular Morita-Baylis-Hillman reaction of ω-formyl-enones. With only 2 mol% of thiourea-phosphine cata-
lyst 3c, chiral functionalized cyclohexenes were achieved under mild reaction conditions with excellent yields and
enantioselectivities.
Keywords allylic alcohol, bifunctional thiourea-phosphine, chiral squaramide, enantioselective organocatalysis,
Morita-Baylis-Hillman reaction
Introduction
CF3
CF3
The asymmetric Morita-Baylis-Hillman (MBH) re-
action is an important C－C bond-forming reaction pro-
viding enantioenriched allylic alcohols, which are useful
building blocks in organic synthesis.[1] Since
Hatakeyama[2] developed the first highly enantioselec-
tive MBH reaction, great progress has been made in the
past decade.[3] To our knowledge, there are but a few
reports concerning the enantioselective intramolecular
MBH reaction. Although the first example of an asym-
metric intramolecular MBH reaction was reported by
Fráter in 1992,[4] this enantioselective reaction was not
explored further until recent decade. In 2005 Hong's
group reported the intramolecular MBH reaction of
hept-2-enedial using proline and imidazole as co-cata-
lyst system.[5] At the same time, Miller's group devel-
oped a co-catalyst system involving pipecolinic acid and
N-methylimidazole for the intramolecular MBH reac-
tion of enone-al.[6] Later, the chiral rhenium-containing
phosphine was used as catalyst for the enantioselective
intramolecular MBH reaction.[7] We have found the
chiral bifunctional phosphines were efficient for the
intramolecular MBH reaction due to the nucleophilic
activation by tertiary phosphine and the electrophilic
activation by hydrogen-bonding (Figure 1).[8] Very re-
cently, Chen and co-workers developed chiral ferro-
cene-based squaramide-phospines as the bifunctional
organocatalyst for the intramolecular MBH reaction.[9]
In addition, resin-supported proline could promote the
intramolecular MBH reaction.[10]
Bn
S
S
N
N
CF3
N
N
CF3
H
H
H
H
PPh2
PPh2
2
1
PPh2
PPh2
H
H
N
H
H
N
O
N
O
N
AcO
AcO
AcO
AcO
S
S
OAc
OAc
OAc
OAc
3a
3b
PPh2
PPh2
H
N
H
N
H
N
H
N
O
O
AcO
AcO
AcO
AcO
S
S
OAc
OAc
3c
OAc
O
OAc
O
3d
PPh2
PPh2
H
N
H
N
H
N
H
N
AcO
AcO
S
S
AcO
OAc
AcO
OAc
3e
OAc
3f
OAc
S
S
S
N
N
H
Ph
N
N
H
Ph
N
H
N
H
H
H
PPh2
PPh2
PPh2
3g
3i
3h
Figure 1 Structures of the chiral thiourea-phosphines.
as an important tool for enantioselective synthesis.[11] It
is demonstrated that introducing a saccharide scaffold
into a bifunctional thiourea was a successful strategy to
Over the last decade, electrophile activation by chiral
hydrogen-bond donors especially thiourea has emerged
*
E-mail: xinyanwu@ecust.edu.cn; Tel.: 0086-021-64252011; Fax: 0086-021-64252758
Received July 1, 2015; accepted September 20, 2015; published online September 29, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500468 or from the author.
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1111

Yang et al.
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design efficient organocatalysts.[12] Compared with the
previously developed tertiary thiourea-phosphine cata-
lysts 1 and 2,[13] saccharide-based thiourea-phosphine
3d was more efficient in the intermolecular MBH reac-
tion with higher reactivity and wider substrate scope
(Figure 1).[14] Inspired by the previous work, we are
interested in evaluating these catalysts in the intramole-
cular MBH reactions. Herein, we report the highly en-
antioselective intramolecular MBH reaction catalyzed
by saccharide-based thiourea-phosphines.
3h bearing a simple chiral group and cyclohexane-based
thiourea-phosphines 3i were also examined, and they
could not provide good enantioselectivity (Entries 7－9).
Compared with thiourea-phosphine 1 and 2 without
saccharide scaffold, D-mannose-based thiourea-phos-
phine 3c displayed a higher effectivity (Entries 3 vs. 10
and 11).[8] Moreover, the catalyst loading of 3c could be
decreased to 3 mol% displaying the same level of cata-
lytic activity (Entry 13 vs. 3).
Table 1 Catalyst screening for the intramolecular MBH reac-
tion of 4aa
Experimental
O
O
O
OH
General procedure for the intramolecular Morita-
Baylis-Hillman reaction: thiourea-phosphine 3c (2.7 mg,
0.004 mmol) and t-BuOH (2.0 mL) were added to a
vessel containing ω-formyl-enone 4[15] (0.2 mmol) at 25
℃. The resulting mixture was stirred at this temperature
until the reaction was completed (monitored by TLC).
Then the solvent was removed under reduced pressure,
and the residue was purified by a flash column chroma-
tography (silica gel, petroleum ether/EtOAc/CH2Cl2 as
the eluent) to afford the desired product.[8a] The ee val-
ues were determined by HPLC analysis with a chiral
column.
10 mol% Catalyst
CH2Cl2, 25 oC
5a
4a
Entry Catalyst
Time/d
Yield b/%
ee c/%
69
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
3
99
92
99
47
43
45
76
61
63
83
99
99
90
2
3
54
3
1.5
3
94
4
−83
−88
−80
4
5
3
† Electronic Supplementary Information (ESI) avail-
able: HPLC spectra for the Morita-Baylis-Hillman
products. See DOI: 10.1039/b000000x/.
6
3
7
4.5
4.5
4.5
0.5
1.5
3
8
12
9
36
Results and Discussion
10
11
12d
13e
1
−76
76
Our initial investigation of enantioselective intra-
molecular MBH reaction of ω-formyl-enone 4a was
performed in CH2Cl2 with 10 mol% thiourea-phosphine
3 at 25 ℃. The results in Table 1 indicted that the sugar
moiety of the catalysts had a remarkable effect on the
reactivity and enantioselectivity of the intramolecular
MBH reaction. The stereochemical control of the reac-
tion resulted from the chirality of the cyclohexyl amino-
phosphine backbone (Entries 1－3 vs. 4－6). All the
selected sugars (D-glucose, D-galactose and D-mannose)
matched with an (R,R)-configuration of cyclohexyl
aminophosphine to accelerate the MBH reaction with
excellent yields (Entries 1－3). In contrast, their di-
astereomers 3d－3f bearing the (S,S)-cyclohexyl amino-
phosphine exhibited poor reactivity (Entries 4－6). On
the other hand, the enantioselectivity of the MBH reac-
tion was highly affected by the configuration at the C1
and C2 carbon atom of the sugar scaffold.[12j,16] Thus
D-mannose-based organocatalyst 3c achieved higher
enantioselectivity than D-glucose-based catalyst 3a and
D-galactose-based catalyst 3b, while organocatalyst 3f
provided lower enantioselectivity than D-glucose de-
rivative 3d and D-galactose derivative 3e. Among the
screened thiourea-phosphine containing saccharide
moiety, D-mannose-based organocatalyst 3c provided
the highest yield and enantioselectivity within 36 h
(99% yield and 94% ee, Entry 3). To further prove the
effect of the sugar scaffold, thiourea-phosphines 3g and
2
3c
3c
91
5
90
a Unless stated otherwise, the reactions were performed on 0.2
mmol scale in 1.0 mL CH2Cl2 (0.2 mol/L) using 10 mol% of
catalyst at 25 ℃. b Isolated yields. c The ee values were deter-
mined by chiral HPLC analysis, and the absolute configuration
was assigned by comparison of optical rotation value with that
reported in literature.[6] d Using 5 mol% 3c as catalyst. e Using 3
mol% 3c as catalyst.
Next, solvent effect was examined in the reaction of
ω-formyl-enone 4a using 3 mol% 3c as the catalyst
(Table 2). The survey of solvents indicated that the
nonpolar solvents, such as n-hexane and toluene, led to
moderate chemical yields (Entries 1 and 2), whereas the
aprotic polar solvents afforded poor yields due to the
low conversion of 4a in these solvents (Entries 5－7).
Comparatively, protic solvents examined except MeOH
were evidently observed to accelerate the reaction rate
(Entries 9－11), which usually possess a deleterious
effect against the Michael additions for destructing the
hydrogen bonds between substrates and the thiourea
moiety.[17] The alcohol has probably acted as a shuttle to
reduce the energy of the proton-transfer to activate
MBH reaction.[18] t-BuOH was indicated to be a better
solvent, leading to the desired product 5a in 90% yield
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Highly Enantioselective Intramolecular Morita-Baylis-Hillman Reaction
and 95% ee within 2 d (Entry 11). The addition of water
to the t-BuOH solution could promote the proton of the
solvent, but it caused a sharp decrease of both yield and
enantioselectivity (Entry 12 vs. 11), which indicated
that water had a negative influence towards the reaction.
To our pleasure, the product 5a could also be obtained
in both excellent yield and enantioselectivity with lower
load of catalyst (2 mol% of 3c, Entry 13). Further de-
creasing the load of 3c to 1 mol% led to the descent of
chemical yield and enantioselectivity (Entry 14). As
indicated in Entry 15, satisfying result could also be
obtained when the concentration was decreased to 0.1
mol/L, leading to 5a with 90% yield and 95% ee.
Therefore, the optimal reaction condition was confirmed
as described in Entry 15.
was gradually enhanced along with the electron enrich-
ment on the phenyl group, while longer reaction times
were required for complete conversion (Entries 9－12
vs. 1). Compared with thiourea-phosphine 1 and 2,[8]
D-mannose-based thiourea-phosphine 3c exhibited bet-
ter substrate generality and enantioselectivity in the in-
tramolecular MBH reaction of ω-formyl-enones. Un-
fortunately, D-mannose-based thiourea-phosphine 3c
was still not efficient for the intramolecular MBH reac-
tion of methyl ω-formyl-enone and phenyl δ-formyle-
none.
Table 3 Substrate scope of intramolecular MBH reaction cata-
lyzed by 3ca
O
OH
O
O
2 mol% 3c
Ar
Table 2 The survey of solvents for the intramolecular MBH
reaction of 4aa
Ar
t-BuOH, 25 oC
4
5
O
O
O
OH
Entry Ar
Time/d
Yieldb/%
90
eec/%
95
3 mol% 3c
Solvent, 25 oC
1
Ph
2
5a
4a
2
2-BrC6H4
3-BrC6H4
4-BrC6H4
3-ClC6H4
4-ClC6H4
4-FC6H4
2
96
29
3
3
92
90
Entry Solvent
Time/d
Yieldb/%
60
eec/%
95
83
86
90
93
90
ndd
6
4
2
92
90
1
n-Hexane
Toluene
CHCl3
CH2Cl2
THF
5
5
5
2.5
2
95
90
92
2
80
6
93
3
5
87
7
2
90
93
4
5
90
8
2-Naphthyl
3-MeC6H4
4-MeC6H4
2
97
96
97
97
99
5
5
21
9
2.5
2.5
4
99
6
CH3CN
DMF
5
10
10
11
12
93
7
4
trace
30
4-MeOC6H4
4-Me2NC6H4
93
8
MeOH
EtOH
5
6
86
99
9
1.5
2
92
70
90
95
66
94
85
95
a The reactions were performed on 0.2 mmol scale in 2.0 mL
t-BuOH (0.1 mol/L) using 2 mol% of catalyst 3c at 25℃. b Iso-
lated yields. c Determined by chiral HPLC analysis.
10
11
12e
13f
14g
15f,h
i-PrOH
t-BuOH
93
2
90
t-BuOH/H2O
t-BuOH
2
65
2
90
Conclusions
t-BuOH
4
84
In conclusion, we have developed a highly enanti-
oselective intramolecular MBH reaction catalyzed by
the D-mannose-based chiral thiourea-phosphine. The
intramolecular MBH reaction of ω-formyl-enones could
be performed efficiently using 2 mol% of thiourea-
phosphine 3c under mild conditions to provide chiral
cyclic allylic alcohols in excellent yields and enantiose-
lectivities. Further applications of the sugar-based chiral
thiourea-phosphines in enantioselective reactions are
currently undergoing in our group.
t-BuOH
2
90
a Unless stated otherwise, the reactions were performed on 0.2
mmol scale in 1.0 mL solvent (0.2 mol/L) using 3 mol% of cata-
lyst 3c at 25 ℃. b Isolated yields. c Determined by chiral HPLC
analysis. d Not determined. 0.5 mL of t-BuOH and 0.5 mL of
e
H2O as solvent. f Using 2 mol% 3c as catalyst. g Using 1 mol% 3c
as catalyst. h The reaction was performed on 0.2 mmol scale in
2.0 mL solvent (0.1 mol/L) at 25 ℃.
Under the optimized reaction conditions, the sub-
strate scope of the intramolecular MBH reaction was
investigated. It is noteworthy that the reactions took
place very efficiently (Table 3, 86%－99% yield) with
excellent levels of enantioselectivity (90%－99% ee)
for all of the screened substrates except ortho-sub-
stituted aryl enone probably due to the ortho effect (En-
try 2 vs. Entries 1 and 3－12). The enantioselectivity
Acknowledgement
We acknowledge the financial support from National
Natural Science Foundation of China (Nos. 20772029,
21242007), the Program for New Century Excellent
Talents in University (No. NCET-07-0286), and the
Fundamental Research Funds for the Central Universi-
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1113

Yang et al.
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(Cheng, F.)
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