Bifunctional (Thio)urea-Phosphine Organocatalysts Derived from d -Glucose and α-Amino Acids and Their Application to the Enantioselective Morita-Baylis-Hillman Reaction

Article abstract of DOI:10.1055/s-0035-1560931

Novel (thio)urea-tertiary phosphines were developed for use as bifunctional organocatalysts readily available from naturally occurring molecules: saccharides and amino acids. The efficiency of the organocatalysts was demonstrated in the asymmetric Morita-

Full text of DOI:10.1055/s-0035-1560931

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2690–2696
letter
2690
I. Gergelitsová et al.
Letter
Synlett
Bifunctional (Thio)urea–Phosphine Organocatalysts Derived from
D-Glucose and α-Amino Acids and Their Application to the Enantio-
selective Morita–Baylis–Hillman Reaction
CH2OR
I. Gergelitsováa
RO
X: S, O
J. Tauchmana
I. Císařováb
J. Veselý*a
O
X
R1
D-glucose
L-α-amino acid
R1 = H, Me, i-Pr
RO
N
N
R = Me, Ac, Bn
H
H
RO
PPh2
a Department of Organic Chemistry, Faculty of Science, Charles
University in Prague, Hlavova 2030/8, 128 43 Praha 2, Czech
Republic
b Department of Inorganic Chemistry, Faculty of Science,
Charles University in Prague, Hlavova 2030/8, 128 43 Praha 2,
Czech Republic
OH
O
10 mol%
O
O
+
Ar
OR2
Ar
H
OR2
jxvesely@natur.cuni.cz
16 examples
up to 85% yield
up to 87% ee
Received: 27.07.2015
Accepted after revision: 02.11.2015
Published online: 09.11.2015
DOI: 10.1055/s-0035-1560931; Art ID: st-2015-b0583-l
Abstract Novel (thio)urea–tertiary phosphines were developed for use
as bifunctional organocatalysts readily available from naturally occur-
ring molecules: saccharides and amino acids. The efficiency of the or-
ganocatalysts was demonstrated in the asymmetric Morita–Baylis–Hill-
man (MBH) reaction of aromatic aldehydes with acrylates. The MBH
products were obtained in good yields (up to 85%) and with high enan-
tioselectivities (up to 87% ee).
Key words organocatalysis, Morita–Baylis–Hillman reactions, phos-
phines, amino acids, asymmetric catalysis
Jan Veselý obtained his Ph.D. in 2005 under the supervision of Prof.
Tomáš Trnka (Charles University in Prague) and Dr. Miroslav Ledvina (In-
stitute of Organic Chemistry and Biochemistry IOCB, AS CR), working on
the synthesis of linear and cyclic oligosaccharides. Then, he worked one
year as a postdoc in the group of Stefan Oscarson, and one and a half
years in the group of Armando Córdova (both at Arrhenius Laboratories,
Stockholm University). After his return, he started an independent re-
search career at the Charles University in Prague, where he currently
holds the position of an associate professor. His research interests are
the stereoselective preparation of sugar-derived building blocks, as well
as the development of new asymmetric methodologies based on or-
ganocatalysis and their application in total synthesis.
Asymmetric catalysis with small organic molecules rep-
resents one of the fundamental pillars in asymmetric syn-
thetic processes.1,2 This rapidly evolving area has already
shown a high synthetic potential in many chemical reac-
tions, including enantioselective formation of single or
multiple carbon–carbon or carbon–heteroatom bonds in
single-step or cascade processes.2a,3 Among the various con-
cepts commonly used in asymmetric organocatalysis, hy-
drogen-bonding catalysis has emerged as a powerful ap-
proach. In particular, (thio)ureas,4 squaramides,5 and guani-
dinium ions6 have proved to be highly promising
organocatalysts. Since the pioneering work of Takemoto
and co-workers,7 which was inspired by the natural oxyan-
ion hole of enzymes, a combination of a hydrogen-bond do-
nor (thio)urea moiety and an amine as a Lewis base in a sin-
gle chiral scaffold has become a popular motif in the devel-
opment of organocatalysts. In contrast to well-developed
bifunctional (thio)ureas derived from cinchona alkaloids,
steroids, or peptides, little attention has been paid to the
synthesis of bifunctional (thio)ureas derived from saccha-
rides.8 In 2007, Kunz and co-workers (inspired by Jacobsen’s
catalysts9) reported efficient bifunctional urea–aldimine
organocatalysts derived from D-glucosamine for enantiose-
lective Strecker reactions.10 Other examples of bifunctional
sugar-derived organocatalysts (thiourea–primary or tertia-
ry amine) were reported by Ma and co-workers; in these
organocatalysts, the carbohydrate unit serves as a bulky
electron-withdrawing group to increase the acidity of the
thiourea.11 Later, Benaglia, Lay, and co-workers investigated
a new family of (thio)urea–amine organocatalysts for the
addition of acetylacetone to nitrostyrene.12 Several other
examples of bifunctional sugar-derived organocatalysts
(thiourea–amine type) have been reported, and their cata-
lytic activities have been investigated.11,13 Compared with
the extensive development carried out on bifunctional
thiourea–amine organocatalysts, the development of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2690–2696

2691
I. Gergelitsová et al.
Letter
Synlett
thiourea–trivalent phosphine organocatalysts remains a
less-explored area, although phosphines belong to an im-
portant class of nucleophilic catalysts.14 Recently, several
bifunctional thiourea–phosphine organocatalysts derived
from natural amino acids,15 or synthetic compounds con-
taining binaphthyl or cyclohexane motifs16,17 have been de-
veloped and applied in a variety of enantioselective organic
reactions. However, only one type of bifunctional thiourea–
phosphine organocatalyst derived from saccharides and a
cyclohexane skeleton has been reported.18
CH2OR1
O
CH2OR1
O
R2
R1O
R1O
R1O
R1O
R3
R2
R3
S
+
CH2Cl2
PPh2
H2N
N
H
N
NCS
H
OR1
PPh2
OR1
3a: R1 = Me 2a: R2 = H, R3 = H
5a: R1 = Me, R2 = R3 = H, (74%)
3b: R1 = Ac 2b: R2 = Me, R3 = H 5b: R1 = Me, R2 = Me, R3 = H, (78%)
3c: R1 = Bn 2c: R2 = i-Pr, R3 = H 5c: R1 = Me, R2 = i-Pr, R3 = H, (72%)
2c': R2 = H, R3 = i-Pr 5c': R1 = Me, R2 = H, R3 = i-Pr, (81%)
5d: R1 = Ac, R2 = i-Pr, R3 = H, (93%)
5e: R1 = Bn, R2 = i-Pr, R3 = H, (73%)
There are no previous reports of bifunctional thiourea–
phosphine organocatalysts consisting of a saccharide unit
and an amino acid derived chiral phosphine, although it is
apparent that, like amino acids, carbohydrates are readily
available chiral scaffolds. In view of these facts, we designed
new types of bifunctional urea– and thiourea–phosphine
organocatalysts 6 and 5 (Scheme 1), and we explored their
efficiency in an enantioselective Morita–Baylis–Hillman
(MBH) reaction.19
Scheme 2 Preparation of thiourea–phosphine organocatalysts 5
On the other hand, the synthesis of the urea–phosphine
catalysts 6 did not required isolation of the intermediate
isocyanates 4′, and was therefore accomplished in two
steps (formylation/condensation) from the corresponding
glycosylamines 4 (Scheme 3).24 Glycosylamines 4 were pre-
pared by catalytic hydrogenation22f of the corresponding
glycosyl azides 1.22c,d All the prepared bifunctional catalysts
were obtained in good to high yields (72–93%), and they ex-
hibit good air and bench stability under standard condi-
tions.
D-glucose
L-α-amino acid
CH2OR
O
CH2OR
R1
RO
RO
RO
RO
X
R1
O
CH2OR
O
CH2OR
O
H2N
N
N
N3
RO
RO
RO
RO
PPh2
H
H
triphosgene
RO
PPh2
OR
1
5 X = S
2
CH2Cl2, aq NaHCO3
NH2
NCO
6 X = O
OR
OR
4a: R = Me
4b: R = Ac
Scheme 1 Novel (thio)urea–phosphine organocatalysts 5 and 6
4'
H2N
Ph2P
CH2OR
In designing the bifunctional organocatalysts 5 and 6,
we chose D-glucose and a set of α-amino acids (glycine,
L-alanine, and L-valine) as readily available starting materi-
als (Scheme 1). As in previous reports,11 the chosen gluco-
pyranosyl unit serves as a bulky electron-withdrawing
group, affording increased (thio)urea acidity, and the cho-
sen phosphines display a remarkable combination of strong
nucleophilicity and stability to air. The phosphines 2, which
display various steric effects from the neighboring alkyl
moiety, were obtained from the corresponding α-amino ac-
ids by using N-tert-butoxycarbonyl or N-tosyl protective
groups.20,21 Isothiocyanates 3, suitable for the construction
of bifunctional thiourea–phosphine catalysts 5, were pre-
pared from D-glucose by using a reported procedure.22 The
thiourea–phosphine organocatalysts 5 were prepared by
simple condensation of the key building blocks 3 and 2, as
shown in Scheme 2.23
RO
RO
O
O
2c
N
N
H
H
CH2Cl2
OR
PPh2
6a: R = Me, (79%)
6b: R = Ac, (60%)
Scheme 3 Preparation of urea–phosphine organocatalysts 6
The catalytic activity of the prepared organocatalysts 5
and 6 was initially evaluated in the MBH reaction of the
model substrates 4-nitrobenzaldehyde (10a) and methyl
acrylate (11a) in tetrahydrofuran at 25 °C. At the outset, we
decided to compare the catalytic efficiency of 5 and 6 with
that of other previously reported organocatalysts 7–9 (Fig-
ure 1).7b,17,25
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2690–2696

2692
I. Gergelitsová et al.
Letter
Synlett
protecting group on the saccharide unit showed a lower re-
activity, probably due to interference of the acetoxy group
and the acidic thiourea group (entry 4). On the other hand,
the presence of a bulkier noninterfering benzyl protecting
group on the saccharide unit had only a limited effect on
the reactivity of catalyst 5e (entry 5). Note that changing
the O-protecting group on the saccharide unit of the cata-
lyst did not affect the stereochemical outcome of the reac-
tion. Catalysts 5a, 5b, and 9 showed similar efficiencies af-
ter 24 hours, including full conversion of the starting mate-
rials (entries 1, 2, and 10). In addition, Wu’s catalyst (9)
gave 12a with high enantioselectivity. Nevertheless, further
modification of the phosphine scaffold of 9 to tune the ste-
reocontrol of the reaction is more complicated than in the
case of our catalysts 5, in which a variety of natural or syn-
thetic amino acid scaffolds can be used.
Encouraged with these results, we examined the effect
of various solvents on the reaction catalyzed by 5c (Table
2).26 Screening of the reaction solvents revealed that the
MBH reaction proceeded well in various ethers (Table 2, en-
tries 2–4), and the best results with respect to efficiency
and enantioselectivity were obtained in tert-butyl methyl
ether (entry 2). In polar aprotic solvents, the model reaction
gave the allylic alcohol 12a in high yields but with lower
enantiocontrol (entries 7 and 8). In protic solvents, low
conversion and low yield of 12a, and no enantiocontrol,
were observed (entry 10).
CF3
N
S
O
H
F3C
N
H
N
H
HO
NMe2
8 (Takemoto)
CH2OAc
N
AcO
AcO
7 (β-ICD)
O
S
N
N
H
H
OAc
PPh2
9 (Wu)
Figure 1 Other organocatalysts used in the MBH reaction
The thiourea catalysts 5 were more reactive than the
urea catalysts 6 and they afforded product 12a with greater
enantioselectivity (Table 1, entries 1–7). Interestingly, the
best enantiocontrol of the MBH reaction was observed with
our thiourea–phosphine catalyst 5c. The asymmetric reac-
tion between 4-nitrobenzaldehyde (10a) and methyl acry-
late (11a) in tetrahydrofuran catalyzed by 5c afforded the
corresponding allylic alcohol 12a in 68% yield and 82% ee
(entry 3).
Table 1 Screening of Catalysts for the MBH Reactiona
O
H
OH
O
Table 2 A Survey of Solvents for the MBH Reaction of 4-Nitrobenzal-
dehyde (10a) with Methyl Acrylate (11a)a
O
5–9 (10 mol%)
OMe
+
OMe
THF, 25 °C
O2N
O
H
NO2
10a
OH
O
O
11a
12a
5c (10 mol%)
OMe
+
OMe
solvent, 25 °C
Entry
Catalyst
Time (h)
Yieldb (%)
eec (%)
O2N
NO2
10a
1
2
3
4
5
6
7
8
9
10
5a
5b
5c
5d
5e
6a
6b
7
24
24
24
24
24
24
24
72
24
24
83
83
68
22
65
25
12
13
0
12
74
82
81
80
45
5
11a
12a
Entry
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
toluene
TBME
i-Pr2O
THF
45
78
49
68
52
59
81
86
68
22
82
86
79
82
70
75
76
72
61
1
6
CH2Cl2
CHCl3
DMF
8
–
9
80
80
a Reaction conditions: 5–9 (10 mol%), 10a (0.1 mmol), 11a (0.5 mmol),
THF (1 mL), 25 °C.
DMSO
MeCN
MeOH
b Isolated yield.
c Determined by HPLC using a chiral IC column.
a Reaction conditions: organocatalyst 5c (10 mol%), 10a (0.1 mmol), 11a
(0.5 mmol), solvent (1 mL), 25 °C, 24 h.
When the diphenylphosphine moiety of the catalyst
was modified, catalysts 5a and 5b showed a higher reactivi-
ty but a lower enantioselectivity (Table 1, entries 1 and 2).
Interestingly, catalyst 5d with an electron-withdrawing O-
b Isolated yield.
c Determined by HPLC using a chiral IC column.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2690–2696

2693
I. Gergelitsová et al.
Letter
Synlett
Further optimization studies showed that the tempera-
ture, the catalyst loading, and the 11/10 ratio had little ef-
fect on the stereocontrol of the reaction, whereas the yield
of the reaction varied significantly with the temperature
and catalyst loading (Supporting Information, Table SI1, en-
tries 1–6). On the basis of these results, we found that the
optimal conditions for the MBH reaction were room tem-
perature, 10 mol% of catalyst 5c, and a 5:1 ratio of 11 and 10
in tert-butyl methyl ether (Table 2, entry 2).
Having established the optimal reaction conditions, we
examined the scope of the MBH reaction by employing a
variety of aldehydes with various steric and electronic
properties. As shown in Table 3, the reactions with aromat-
ic aldehydes 10 gave the corresponding alcohols 12 in mod-
erate to high yields and with good enantioselectivities. The
electronic properties and location of the substituents on
the aromatic moiety had obvious effects on the rate, effi-
ciency, and selectivity of the MBH reaction. Substrates with
electron-withdrawing groups, such as nitro, cyano, or tri-
fluoromethyl groups, gave the corresponding alcohols 12a–
e in good yields and with high enantioselectivities (Table 3,
entries 1–5). However, halogenated substrates (F, Cl, Br) re-
acted significantly more slowly, giving lower yields of allylic
alcohols 12g–i with moderate enantiomeric excesses (en-
tries 7–9). In addition, aromatic aldehydes bearing hetero-
cyclic rings were also found to be suitable substrates (en-
tries 11 and 12). When aliphatic aldehydes were employed,
the corresponding MBH alcohols were not obtained, even
after a prolonged reaction time, and decomposition of the
starting material was observed instead.
Table 3 Substrate Scope of the MBH Reactiona
OH
O
O
O
5c (10 mol%)
+
Ar
OR
Ar
H
OR
TBME, 25 °C
10
Entry Ar
11
12,13
R
Time (d) Product Yieldb (%)
eec (%)
1
4-O2NC6H4
2-O2NC6H4
3-O2NC6H4
4-NCC6H4
4-F3CC6H4
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
1
2
1
1
4
7
4
4
4
4
4
4
1
1
1
2
1
12a
12b
12c
12d
12e
12f
76
69
62
77
70
15
24
24
36
29
78
24
70
75
83
76
86
62
82
84
82
77
59
69
71
67
73
73
85
87
80
85
–85
2
3
4
5
6
7
4-FC6H4
12g
12h
12i
8
4-ClC6H4
4-BrC6H4
2-naphthyl
3-pyridyl
2-furyl
9
10
11
12
13
14
15
16
17d
12j
12k
12l
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
13a
13b
13c
13d
Bu
Bn
t-Bu
Me
ent-12a 85
a Reaction conditions: organocatalyst 5c (10 mol%), 10 (0.1 mmol), 11 (0.5
mmol), t-BuOMe (1 mL), 25 °C.
b Isolated yield.
c Determined by HPLC analysis using a chiral column.
d The reaction was performed with organocatalyst 5c′ (10 mol%).
We also examined the MBH reaction of various acrylates
11, catalyzed by 5c (Table 3, entries 13–16). The alkyl group
of the ester moiety had a significant effect on the reaction
rate, but only a limited effect on the enantioselectivity of
the reaction. With bulkier ester moieties, such as tert-butyl,
the reaction rate decreased. The alcohol 13d was obtained
after a prolonged reaction time (2 days) in good yield (76%)
and with high enantioselectivity (85% ee; entry 16).
To confirm the influence of the aminophosphine seg-
ment of the catalyst in controlling the enantioselectivity
and efficiency of the reaction, we prepared catalyst 5c′, de-
rived from D-valine and D-glucose. The asymmetric reaction
between 4-nitrobenzaldehyde (10a) and methyl acrylate
(11a) in tert-butyl methyl ether catalyzed by 5c′ gave the
corresponding allylic alcohol ent-12a in 85% yield and with
–85% ee (Table 3, entry 17). This observation confirmed the
key role of the aminophosphine portion of the catalyst in
enantiocontrol of the reaction.
The absolute configuration of the MBH adducts was
confirmed by chemical correlation with data reported pre-
viously.25,27 The structure of the organocatalysts 5 and 6
was confirmed by a single-crystal X-ray diffraction analysis
of 6a (Figure 2).
Figure 2 View of molecule 6a with the atom-numbering scheme; dis-
placement ellipsoids are drawn at a 30% probability level
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2690–2696

2694
I. Gergelitsová et al.
Letter
Synlett
In summary, we designed and prepared bifunctional
(thio)urea–tertiary phosphine organocatalysts, which were
readily available from naturally occurring biomolecules
such as D-glucose, glycine, L-alanine, and L-valine. The effi-
ciency of our organocatalysts in asymmetric MBH reactions
was compared with that of other catalysts used previously.
The L-valine-derived bifunctional thiourea–phosphine cata-
lyst was found to be highly efficient in the MBH reaction,
giving the MBH adducts with good to high yields (up to
85%) and high enantioselectivities (up to 87% ee).
(4) For selected reviews, see: (a) Fang, X.; Wang, C.-J. Chem.
Commun. 2015, 51, 1185. (b) Zhang, Z.; Bao, Z.; Xing, H. Org.
Biomol. Chem. 2014, 12, 3151. (c) Takemoto, Y. Chem. Pharm.
Bull. 2010, 58, 593. (d) Knowles, R. R.; Jacobsen, E. N. Proc. Natl.
Acad. Sci. U.S.A. 2010, 107, 20678. (e) Zhang, Z.; Schreiner, P. R.
Chem. Soc. Rev. 2009, 38, 1187. (f) Connon, S. J. Chem. Commun.
2008, 2499. (g) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107,
5713. (h) Connon, S. J. Chem. Eur. J. 2006, 12, 5418. (i) Takemoto,
Y. Org. Biomol. Chem. 2005, 3, 4299.
(5) For illustrative reviews, see: (a) Auvil, T. J.; Schafer, A. G.;
Mattson, A. E. Eur. J. Org. Chem. 2014, 2014, 2633. (b) Tsakos, M.;
Kokotos, C. G. Tetrahedron 2013, 69, 10199. (c) Alemán, J.; Parra,
A.; Jiang, H.; Jørgensen, K. A. Chem. Eur. J. 2011, 17, 6890.
(d) Storer, R. I.; Aciro, C.; Jones, L. H. Chem. Soc. Rev. 2011, 40,
2330.
Acknowledgment
(6) For recent reviews on chiral guanidine catalysts, see: (a) Selig, P.
Synthesis 2013, 45, 703. (b) Fu, X.; Tan, C.-H. Chem. Commun.
2011, 47, 8210. (c) Leow, D.; Tan, C.-H. Chem. Asian J. 2009, 4,
488. (d) Ishikawa, T.; Kumamoto, T. Synthesis 2006, 737. For a
comprehensive book, see: (e) Superbases for Organic Synthesis:
Guanidines, Amidines, Phosphazenes and Related Organocata-
lysts; Ishikawa, T., Ed.; Wiley: Chichester, 2009.
(7) (a) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.-N.; Takemoto, Y.
J. Am. Chem. Soc. 2005, 127, 119. (b) Okino, T.; Hoashi, Y.;
Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672.
The authors gratefully acknowledge financial support from the
Charles University Grant Agency (Project No. 704213). This publica-
tion is also a result of the project implementation Support of Estab-
lishment, Development, and Mobility of Quality Research Teams at
the Charles University (project number CZ.1.07/2.3.00/30.0022), sup-
ported by the Education for Competitiveness Operational Programme
(ECOP) and co-financed by the European Social Fund and the state
budget of the Czech Republic.
(8) For a representative book on hydrogen-bonding catalysis, see:
Hydrogen Bonding in Organic Synthesis; Pihko, P. I., Ed.; Wiley-
VCH: Weinheim, 2009.
(9) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.
(10) Becker, C.; Hoben, C.; Kunz, H. Adv. Synth. Catal. 2007, 349, 417.
(11) (a) Li, X.; Liu, K.; Ma, H.; Nie, J.; Ma, J.-A. Synlett 2008, 3242.
(b) Liu, K.; Cui, H.-F.; Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org.
Lett. 2007, 9, 923.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560931.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
Primary Data
for this article are available online at http://www.thieme-con-
nect.com/products/ejournals/journal/10.1055/s-00000083 and can
be cited using the following DOI: 10.4125/pd0074th.
(12) Puglisi, A.; Benaglia, M.; Raimondi, L.; Lay, L.; Poletti, L. Org.
Biomol. Chem. 2011, 9, 3295.
P
m
riarDyat
P
m
riarDyat
1
04.1
2
5
p/
d
0
0
7
4
htP
m
.riary
D
at
Z
a
heln
1
0
1
C
h
e
mstiry
(13) (a) Ágoston, K.; Fügedi, P. Carbohydr. Res. 2014, 389, 50.
(b) Kong, S.; Fan, W.; Wu, G.; Miao, Z. Angew. Chem. Int. Ed.
2012, 51, 8864. (c) Ma, H.; Liu, K.; Zhang, F.-G.; Zhu, C.-L.; Nie, J.;
Ma, J.-A. J. Org. Chem. 2010, 75, 1402. (d) Lu, A.; Gao, P.; Wu, Y.;
Wang, Y.; Zhou, Z.; Tang, C. Org. Biomol. Chem. 2009, 7, 3141.
(e) Gao, P.; Wang, C.; Wu, Y.; Zhou, Z.; Tang, C. Eur. J. Org. Chem.
2008, 4563. (f) Wang, C.; Zhou, Z.; Tang, C. Org. Lett. 2008, 10,
1707.
(14) For illustrative reviews on nucleophilic phosphine organocata-
lysts, see: (a) Methot, L.; Roush, W. R. Adv. Synth. Catal. 2004,
346, 1035. (b) Xiao, Y.; Sun, Z.; Guo, H.; Kwon, O. Beilstein J. Org.
Chem. 2014, 10, 2089.
(15) For representative examples of thiourea–phosphine organocat-
alysts derived from amino acids, see: (a) Yao, W.; Dou, X.; Lu, Y.
J. Am. Chem. Soc. 2015, 137, 54. (b) Wang, T.; Yao, W.; Zhong, F.;
Pang, G. H.; Lu, Y. Angew. Chem. Int. Ed. 2014, 53, 2964.
(c) Zhong, F.; Dou, X.; Han, X.; Yao, W.; Zhu, Q.; Meng, Y.; Lu, Y.
Angew. Chem. Int. Ed. 2013, 52, 943. (d) Han, X.; Zhong, F.; Wang,
Y.; Lu, Y. Angew. Chem. Int. Ed. 2012, 51, 767. (e) Hu, F.; Wei, Y.;
Shi, M. Tetrahedron 2012, 68, 7911. (f) Zhong, F.; Han, X.; Wang,
Y.; Lu, Y. Angew. Chem. Int. Ed. 2011, 50, 7837. (g) Han, X.; Wang,
T.; Zhong, F.; Lu, Y. J. Am. Chem. Soc. 2011, 133, 1726. (h) Wang,
S.-X.; Han, X.; Zhong, F.; Wang, Y.; Lu, Y. Synlett 2011, 2766.
(16) For representative examples of thiourea–phosphine organocat-
alysts derived from a binaphthyl motif, see: (a) Zhang, X.-N.;
Shi, M. ACS Catal. 2013, 3, 507. (b) Deng, H.-P.; Shi, M. Eur. J. Org.
Chem. 2012, 183. (c) Deng, H.-P.; Wei, Y.; Shi, M. Adv. Synth.
References and Notes
(1) For recent comprehensive books, see: (a) Comprehensive Enanti-
oselective Organocatalysis: Catalysts, Reactions and Applications;
Vol. 3; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2013.
(b) Stereoselective Organocatalysis: Bond Formation Methodolo-
gies and Activation Modes; Rios, R. T., Ed.; Wiley: Hoboken,
2013. (c) Science of Synthesis: Asymmetric Organocatalysis; Vols
1–2; List, B.; Maruoka, K., Eds.; Thieme: Stuttgart, 2012.
(d) Enantioselective Organocatalyzed Reactions; Mahrwald, R.,
Ed.; Springer: Berlin, 2011.
(2) For illustrative reviews, see: (a) Volla, C. M. R.; Atodiresei, I.;
Rueping, M. Chem. Rev. 2014, 114, 2390. (b) Scheffler, U.;
Mahrwald, R. Chem. Eur. J. 2013, 19, 14346. (c) Alemán, J.;
Cabrera, S. Chem. Soc. Rev. 2013, 42, 774. (d) Melchiorre, P.
Angew. Chem. Int. Ed. 2012, 51, 9748. (e) Bernardi, L.; Fochi, M.;
Franchini, M. C.; Ricci, A. Org. Biomol. Chem. 2012, 10, 2911.
(f) Wende, R. C.; Schreiner, P. R. Green Chem. 2012, 14, 1821.
(g) Vaxelaire, C.; Winter, P.; Christmann, M. Angew. Chem. Int.
Ed. 2011, 50, 3605.
(3) For selected reviews on organocatalytic cascade reactions, see:
(a) Pellissier, H. Adv. Synth. Catal. 2012, 354, 237. (b) Alba, A.-N.;
Companyo, X.; Viciano, M.; Rios, R. Curr. Org. Chem. 2009, 13,
1432. (c) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem.
Int. Ed. 2007, 46, 1570.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2690–2696

2695
I. Gergelitsová et al.
Letter
Synlett
Catal. 2012, 354, 783. (d) Deng, H.-P.; Wei, Y.; Shi, M. Eur. J. Org.
Chem. 2011, 2011, 1956. (e) Wei, Y.; Shi, M. Acc. Chem. Res. 2010,
43, 1005. (f) Shi, Y.-L.; Shi, M. Adv. Synth. Catal. 2007, 349, 2129.
(17) For representative examples of thiourea–phosphine organocat-
alysts derived from cyclohexane motif, see: (a) Yuan, K.; Song,
H.-L.; Hu, Y.; Fang, J.-F.; Wu, X.-Y. Tetrahedron: Asymmetry 2010,
21, 903. (b) Mita, T.; Jacobsen, E. N. Synlett 2009, 1680.
(c) Yuang, K.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetrahedron 2009, 65,
8185. (d) Fang, Y.-Q.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130,
5660. (e) Yuan, K.; Zang, L.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetra-
hedron Lett. 2008, 49, 6262.
2833, 2902, 2929, 2953, 3052, 3072, 3306 cm−1
.
1H NMR (600
MHz, CDCl3): δH = 7.55–7.49 (m, 2 H), 7.48–7.41 (m, 2 H), 7.37–
7.27 (m, 6 H), 7.14 (br s, 1 H), 6.24 (br s, 1 H), 4.46 (br s, 1 H),
4.38 (br s, 1 H), 3.63 (s, 3 H), 3.60 (s, 3 H), 3.58 (dd, J = 14.3, 3.7
Hz, 1 H), 3.50 (s, 3 H), 3.48 (dd, J = 10.5, 5.5 Hz, 1 H), 3.33 (ddd,
J = 9.7, 5.2, 1.9 Hz, 1 H), 3.26 (s, 3 H), 3.23–3.11 (m, 3 H), 2.39–
2.26 (m, 2 H), 2.16 (dq, J = 13.3, 6.8 Hz, 1 H), 0.89 (d, J = 6.9 Hz, 3
H), 0.87 (d, J = 6.8 Hz, 3 H). 13C{1H} NMR (151 MHz, CDCl3): δC =
183.7 (s), 138.5 (d, J = 15.6 Hz), 138.3 (d, J = 12.0 Hz), 133.0 (s),
132.9 (s), 128.6 (s), 128.5–128.3 (m), 87.1 (s), 84.1 (s), 81.9 (s),
79.5 (s), 76.4 (s), 70.9 (s), 60.8 (s), 60.7 (s), 60.5 (s), 59.0 (s), 58.0
(d, J = 14.0 Hz), 31.4 (d, J = 6.5 Hz), 31.2 (d, J = 13.6 Hz), 18.6 (s),
17.5 (s). 31P{1H} NMR (121 MHz, CDCl3): δP −24.4. HRMS
(ESI-TOF): m/z [M + H]+ calcd for C28H42N2O5PS: 549.2546;
found: 549.2546.
(18) Yang, W.; Sha, F.; Zhang, X.; Yuan, K.; Wu, X. Chin. J. Chem. 2012,
30, 2652.
(19) For selected examples of enantioselective MBH reactions cata-
lyzed by chiral phosphines, see: (a) Wei, Y.; Shi, M. Chem. Asian
J. 2014, 9, 2720. (b) Wei, Y.; Shi, M. Chem. Rev. 2013, 113, 6659.
(c) Zhong, F.; Wang, Y.; Han, X.; Huang, K.-W.; Lu, Y. Org. Lett.
2011, 13, 1310. (d) Han, X.; Wang, Y.; Zhong, F.; Lu, Y. Org.
Biomol. Chem. 2011, 9, 6734. (e) Song, H.-L.; Yuan, K.; Wu, X.-Y.
Chem. Commun. 2011, 47, 1012. (f) Lei, Z.-Y.; Liu, X.-G.; Shi, M.;
Zhao, M. Tetrahedron: Asymmetry 2008, 19, 2058. (g) Shi, M.;
Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 3790.
(h) Hayase, T.; Shibata, T.; Soai, K.; Wakatsuki, Y. Chem.
Commun. 1998, 1271.
(20) For the preparation of 2b, see: (a) Čaplar, V.; Žinić, M.; Pozzo, J.-
L.; Fages, F.; Mieden-Gundert, G.; Vögtle, F. Eur. J. Org. Chem.
2004, 2004, 4048. (b) Douat-Casassus, C.; Pulka, K.; Claudon, P.;
Guichard, G. Org. Lett. 2012, 14, 3130. (c) Wessig, P.; Schwarz, J.
Synlett 1997, 8, 893. (d) Kawamura, K.; Fukuzawa, H.; Hayashi,
M. Org. Lett. 2008, 10, 3509. (e) Anderson, J. C.; Cubbon, R. J.;
Harling, J. D. Tetrahedron: Asymmetry 2001, 12, 923.
(24) N-[({(1S)-1-[(Diphenylphosphino)methyl]-2-methylpropyl}-
amino)carbonyl]-2,3,4,6-tetra-O-methyl-β-D-glucopyrano-
sylamine (6a); Typical Procedure for the Synthesis of the
Urea Catalysts
Amine 4a (100.0 mg, 0.43 mmol) and triphosgene (126.2 mg,
0.43 mmol) were added to a mixture of CH2Cl2 (3 mL) and sat.
aq NaHCO3 (1 mL), and the mixture was stirred at r.t. for 2 h. The
resulting mixture was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried (MgSO4) and concentrated,
and the residue was dissolved in CH2Cl2 (1 mL). A solution of
aminophosphine 2c (86.8 mg, 0.32 mmol) in CH2Cl2 (1 mL) was
added dropwise, and the mixture was stirred at r.t. for 18 h. The
resulting mixture was concentrated, and the residue was puri-
fied by flash column chromatography [silica gel, hexane–EtOAc
(1:1)]. The product was crystallized (CHCl3) to give a white
glacial solid; yield: 124.0 mg (79%); mp 137–138 °C;
[α]D25 +22.6 (c 0.27, CHCl3). IR (KBr, acetone): 510, 701, 740,
934, 952, 988, 1027, 1069, 1099, 1144, 1165, 1186, 1242, 1263,
1308, 1368, 1389, 1416, 1437, 1464, 1482, 1565, 1640, 1811,
1888, 1957, 2830, 2893, 2905, 2932, 2956, 3046, 3072, 3309
(21) For the preparation of 2c and 2c′, see ref. 20d and: Nakamura,
M.; Hatakeyama, T.; Hara, K.; Nakamura, E. J. Am. Chem. Soc.
2003, 125, 6362.
(22) (a) Tsuji, M.; Yamazaki, H. EP 1041080, 2000. For the prepara-
tion of 3b, see: (b) Kühne, M.; Györgydeák, Z.; Lindhorst, T. K.
Synthesis 2006. 949 For the preparation of 3a and 3c, see:
(c) Benoist, E.; Coulais, Y.; Almant, M.; Kovensky, J.; Moreau, V.;
Lesur, D.; Artigau, M.; Picard, C.; Galaup, C.; Gouin, S. G. Carbo-
hydr. Res. 2011, 346, 26. (d) Praly, J.-P.; Senni, D.; Faure, R.;
Descotes, G. Tetrahedron 1995, 51, 1697. (e) André, S.;
Grandjean, C.; Gautier, F.-M.; Bernardi, S.; Sansone, F.; Gabius,
H.-J.; Ungaro, R. Chem. Commun. 2011, 47, 6126. (f) Kuijpers, B.
H. M.; Groothuys, S.; Soede, A. C.; Laverman, P.; Boerman, O. C.;
van Delft, F. L.; Rutjes, F. P. J. T. Bioconjugate Chem. 2007, 18,
1847.
1
cm−1. H NMR (600 MHz, CDCl3): δH = 7.47 (tt, J = 5.1, 2.0 Hz, 2
H), 7.41 (tt, J = 6.0, 2.3 Hz, 2 H), 7.36–7.27 (m, 6 H), 4.98 (d,
J = 6.9 Hz, 1 H), 4.82 (d, J = 7.0 Hz, 1 H), 4.61 (t, J = 8.0 Hz, 1 H),
3.75 (br s, 1 H), 3.64 (s, 3 H), 3.60 (dd, J = 10.4, 2.0 Hz, 1 H), 3.54
(s, 3 H), 3.53–3.50 (m, 1 H), 3.52 (s, 3 H), 3.31 (s, 3 H), 3.24 (t,
J = 8.9 Hz, 1 H), 3.21–3.15 (m, 1 H), 2.98 (t, J = 8.9 Hz, 1 H), 2.23
(d, J = 7.2 Hz, 2 H), 2.02–1.94 (m, 1 H), 0.85 (d, J = 1.1 Hz, 3 H),
0.84 (d, J = 1.2 Hz, 3 H). 13C{1H} NMR (151 MHz, CDCl3): δC
=
157.0 (s), 138.7 (d, J = 12.5 Hz), 132.9 (d, J = 19.3 Hz), 132.8 (d,
J = 19.1 Hz), 128.7–128.4 (m), 87.1 (s), 82.7 (s), 82.0 (s), 79.4 (s),
75.8 (s), 70.9 (s), 60.7 (s), 60.4 (s), 60.2 (s), 59.1 (s), 52.9 (d,
J = 14.2 Hz), 32.2 (s), 32.05 (d, J = 7.8 Hz), 18.9 (s), 17.3 (s).
31P{1H} NMR (121 MHz, CDCl3): δP = −23.7. HRMS (ESI-TOF): m/z
[M + H]+ calcd for C28H42N2O6P: 533.2775; found: 533.2776.
(25) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am.
Chem. Soc. 1999, 121, 10219.
(23) N-[({(1S)-1-[(Diphenylphosphino)methyl]-2-methylpropyl}-
amino)carbonothioyl]-2,3,4,6-tetra-O-methyl-β-D-glucopy-
ranosylamine (5c); Typical Procedure for the Synthesis of the
Thiourea Catalysts
Isothiocyanate 3a (1.16 g, 4.20 mmol) was dissolved in dry
CH2Cl2 (10 mL) under argon in a dry Schlenk flask. A solution of
aminophosphine 2c (1.14 g, 4.20 mmol) in dry CH2Cl2 (10 mL)
was slowly added from a syringe, and the mixture was stirred at
r.t. for 5 h. The solvent was removed under reduced pressure,
and the residue was purified by flash column chromatography
[silica gel, hexane–EtOAc (4:1 to 1:1)] to give a colorless viscous
oil that was freeze-dried to give a white solid; yield: 1.65 g
(72%); [α]D25 −26.1 (c 0.35, CHCl3). IR (KBr): 507, 698, 740, 937,
985, 1030, 1096, 1165, 1186, 1251, 1308, 1347, 1368, 1389,
1431, 1455, 1479, 1541, 1550, 1616, 1739, 1814, 1885, 1960,
(26) Methyl 2-[(R)-Hydroxy(4-nitrophenyl)methyl]acrylate (12a);
Typical Procedure for the Asymmetric MBH Reaction
Acrylate 11a (43.0 mg, 0.50 mmol) was added to a solution of
organocatalyst 5c (5.5 mg, 0.01 mmol) in t-BuOMe (1 mL) at r.t.,
and the solution was stirred for 15 min. Aldehyde 10a (15.1 mg,
0.10 mmol) was added, and mixture was stirred at 25 °C for 1 d
(Table 3). The solvent was removed under reduced pressure, and
the residue was purified by flash column chromatography
[silica gel, hexane–EtOAc (4:1)] to give a yellow solid; yield:
18.1 mg (76%); [α]D25 −57.3 (c 0.52, MeOH, 86% ee). 1H NMR
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2690–2696

2696
I. Gergelitsová et al.
Letter
Synlett
(600 MHz, CDCl3): δH = 8.22 (d, J = 8.7 Hz, 2 H), 7.59 (d, J = 8.6
Hz, 2 H), 6.41 (s, 1 H), 5.89 (s, 1 H), 5.64 (d, J = 6.1 Hz, 1 H), 3.76
(s, 3 H), 3.34 (d, J = 6.3 Hz, 1 H). 13C{1H} NMR (151 MHz, CDCl3):
δC = 166.4, 148.5, 147.5, 140.9, 127.3, 123.6, 72.8, 52.2. MS (EI-
TOF): m/z = 237.1 [M]+•. HPLC (ChiralPak IC column, heptane–
i-PrOH (80:20), flow rate: 1.0 mL/min, λ = 220 nm): tR = 6.69
min (minor), 8.04 min (major).
(27) Drewes, S. E.; Emslie, N. D.; Field, J. S.; Khan, A. A.; Ramesar, N.
Tetrahedron: Asymmetry 1992, 3, 255.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2690–2696