Highly enantioselective Diels-Alder reaction of Danishefsky-type diene and electron-deficient olefins catalyzed by an Yb(III)/chiral bis-urea complex

Article abstract of DOI:10.1016/j.tetlet.2009.07.110

The synthesis and utility of the novel axially chiral bis-urea ligand BINUREA are described. A complex of this urea ligand with ytterbium triflate and DBU can be used in the catalytic enantioselective Diels-Alder reaction of Danishefsky-type diene and ele

Full text of DOI:10.1016/j.tetlet.2009.07.110

Tetrahedron Letters 50 (2009) 5652–5655
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Highly enantioselective Diels–Alder reaction of Danishefsky-type diene and
electron-deficient olefins catalyzed by an Yb(III)/chiral bis-urea complex
*
Shinji Harada, Nozomi Toudou, Shiharu Hiraoka, Atsushi Nishida
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and utility of the novel axially chiral bis-urea ligand BINUREA are described. A complex of
this urea ligand with ytterbium triflate and DBU can be used in the catalytic enantioselective Diels–Alder
reaction of Danishefsky-type diene and electron-deficient olefins to give the adducts in good to excellent
yield and enantiomeric excess (ee).
Received 29 June 2009
Revised 17 July 2009
Accepted 18 July 2009
Available online 24 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Here, we report the synthesis of the new bis-urea ligand BINU-
REA and its application to the ytterbium(III)-catalyzed enantiose-
Urea is a ubiquitous functional group in organic and inorganic
chemistries, and has many uses. In the area of synthetic organic
chemistry, (thio)ureas can be used as organocatalysts and have fas-
cinated many scientists.1 Such catalysis features the hydrogen
bond-donating ability of the NH moiety to activate electrophiles.2
This ability to act as hydrogen-bond donors enables (thio)ureas
to function as anion-recognizing agents.3 While these acidic prop-
erties of (thio)ureas are quite useful, ureas can also be used as a Le-
wis base for catalytic reactions.4 Their coordinative nature shows
that they can be very useful as a polar solvent and as an additive
to metal catalysis.5 In addition, thioureas have been shown to be
efficient and air-stable ligands of transition metals.6,7 However,
there are few examples of the effective application of chiral ureas
as ligands to metal-catalyzed asymmetric reactions.8
lective Diels–Alder reaction of Danishefsky-type dienes with
electron-deficient alkenes. We found that the new chiral bis-urea
ligand led to good to excellent conversions and enantioselectivities
in the Diels–Alder reaction, which were similar to or even higher
than those with Yb(III)/BINAMIDE catalyst.
To develop new ligands with a urea functionality, we chose
biphenyl and binaphthyl as backbones and chiral sources following
the structure of BINAMIDE, and planned to synthesize them from
optically active biphenyldiamine 6 and binaphthyldiamine 7 with
isocyanates. However, a method for the synthesis of optically ac-
tive biphenyldiamine 6 has not been established.15 Thus, we first
attached a chiral side-chain on urea expecting to separate each dia-
stereomer after urea formation.
Commercially available chiral isocyanate 8 was stirred with ( )-
biphenyldiamine16 in dichloromethane at room temperature to
give the desired bis-urea ligands in good yield. (R)-9 and (S)-9 were
We recently reported the Yb(III)/BINAMIDE 1 complex, which
catalyzed the asymmetric Diels–Alder reaction of electron-defi-
cient olefins and 1-methoxy-3-trialkylsiloxy-1,3-butadienes
2
(Danishefsky-type dienes9).10,11 Due to the instability of the dienes
under acidic conditions, the Lewis acid-catalyzed Diels–Alder reac-
tion using Danishefsky-type dienes had been quite difficult.12 To
overcome this problem, the use of lanthanide salts was the key
to promoting the desired reaction, as first reported by Inokuchi’s
group.13 Based on their results, we developed Yb(III)/BINAMIDE
catalyst, which was prepared from Yb(OTf)3, BINAMIDE 1a, and
DBU.14 While the Diels–Alder reaction of several kinds of alkenes
with Danishefsky-type dienes was efficiently facilitated by the cat-
alyst to give the exo adduct, the scope of substrates was still unsat-
isfactory (Scheme 1). Therefore, further optimization of the
catalyst was necessary.
Yb(OTf)3 (x mol %)
BINAMIDE 1 (1.2x mol %)
DBU (2.4x mol %)
SiO
O
O
SiO
R
+
R
N
O
O
N
CH2Cl2, 0 ºC
(x: 5-10)
OMe
OMe O
O
2
3
exo only
4
(2 equiv.)
X
O
TFA
NH
NH
O
O
R
O
X
N
O
O
(S)-BINAMIDE
1a: X=3,5-difluoro
y: 29-97%
41-94% ee
5
* Corresponding author. Tel.: +81 43 290 2907; fax: +81 43 290 2909.
E-mail address: nishida@p.chiba-u.ac.jp (A. Nishida).
Scheme 1. Asymmetric Diels–Alder reaction of Danishefsky-type dienes catalyzed
by Yb(III)/BINAMIDE complex.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.110

S. Harada et al. / Tetrahedron Letters 50 (2009) 5652–5655
5653
Table 1
Screening conditions
obtained in a 1:1 mixture (total 94% yield), and were easily sepa-
rated by silica gel column chromatography (Scheme 2).17 Starting
from commercially available chiral (R)-binaphthyldiamine (7), li-
gand (R)-10a was synthesized. ((S)-10a was also prepared from
(S)-diamine following the same procedure.)
1)
Yb(OTf)3 (10 mol %)
ligand (x mol %)
DBU (y mol %)
Me
O
TBSO
O
O
CH2Cl2, 0 ºC, time
+
N
O
Me
N
O
2) TFA, CH2Cl2
rt, 10 min
We prepared other ligands with different substituents 10b–10e
by the condensation of diamine and the corresponding isocyanates
to study the effects of their structure on both the catalytic activity
and selectivity in the ytterbium-catalyzed Diels–Alder reaction,
and also synthesized thiourea derivatives 11a and 11b (Fig. 1).
As an initial screening, synthesized bis-urea ligand was used in
the catalytic asymmetric Diels–Alder reaction of Danishefsky-type
diene 2a and electron-deficient olefin 3a. The reaction using
Yb(OTf)3, ligand (R)-9, and DBU (1/1.2/2.4: best ratio in the
Yb(III)/BINAMIDE/DBU system) proceeded sluggishly to afford the
adduct 5a in 2% yield with low enantioselectivity (38% ee). (S)-9
showed a similar reactivity and selectivity (3% yield; 31% ee). For
the binaphthyl derivatives (R)- and (S)-10a, matched and mis-
matched combinations were observed (Table 1, entries 3 and 4),
but the results were better than those with their biphenyl deriva-
tives (yields of 18% and 7%, respectively). In these entries, the abso-
lute configuration of the products was regulated by the axial
chirality of the ligands. We used the new bis-urea ligand (R)-10a
as a tentative ligand, and precisely surveyed the reaction condi-
tions. This catalyst system was quite sensitive to the relative ratio
of each reagent, and both the reactivity and selectivity were dra-
matically affected. After an extensive investigation, the best ratio
was found to be Yb(OTf)3/(R)-10a/DBU = 1/1/2, as shown in entry
5 (99% yield; 98% ee).18 Notably, Yb(OTf)3 and each of the ligands
were heated at 120 °C under reduced pressure (<0.1 mmHg) before
use,19 and cyclohexene product 4a was obtained as a single diaste-
reomer in each case. The effects of the substituent on urea were
O
O
OMe
2a
3a
5a
(2 equiv.)
a
Entry
Ligand (x mol %)
DBU (y mol %)
Time (h)
Yield (%)
% ee
1
2
3
4
5
6
7
8
9
(R)-9 (12)
(S)-9 (12)
24
24
24
24
20
20
20
20
20
20
20
4
4
4
4
2
3
3
3
3
3
3
2
3
18
7
99
22
93
20
45
37
46
38
–31
96
–91
98
39
94
14
96
27
37
(R)-10a (12)
(S)-10a (12)
(R)-10a (10)
(R)-10b (10)
(R)-10c (10)
(R)-10d (10)
(R)-10e (10)
(R)-11a (10)
(R)-11b (10)
10
11
a
In all entries, cyclohexene adduct 4a was obtained as a single diastereomer.
then evaluated. Aromatic substituents (Ph: 10b) lowered both
the reactivity and selectivity (entry 6). Benzyl 10c showed good
reactivity and selectivity (entry 7), but did not give better results
than
a-methylbenzyl 10a. Interestingly, a,a-dimethylbenzyl 10d
afforded an almost racemic product, and naphthyl derivative 10e
resulted in modest yield. For thiourea analogues, both 11a and
11b resulted in low yields and ees. Among the ligands tested, an
-methylbenzyl side chain proved to be the most active and most
selective.20
With the optimal reaction conditions in hand, the substrate
generality was explored. First, the reaction of a variety of dieno-
philes with linear alkyl chains 3a–3e was examined. The reactions
proceeded smoothly to afford the products in good to excellent
yields (Table 2, entries 1–5). The enantioselectivities were all bet-
ter than those with the Yb(III)/BINAMIDE 1a system. For substrates
with a conjugated double bond (3f: entry 6) or chlorine atom (3g:
entry 7), however, the reactions did not run to completion. The
a
O
Me
N
H
N
H
Ph
Ph
H
H
N
N
Me
Ph
O
Me
Me
(R)-9
O
Me
Me
NH2
NH2
+
•
+
CH2Cl2
rt, 8 h
N
O
N
H
N
H
Ph
Ph
(2.2 equiv)
Table 2
94%
Substrate scope and limitations
8
Biphenyldiamine 6
H
H
(R)-9:(S)-9
N
N
(racemate)
=1:1
1)
Yb(OTf)3 (10 mol %)
(R)-10a (10 mol %)
DBU (20 mol %)
O
Me
(S)-9
O
R
TBSO
O
O
CH2Cl2, 0 ºC, 3 h
+
N
O
O
Me
R
N
O
2) TFA, CH2Cl2
rt, 10 min
O
5
O
N
N
H
Ph
Ph
Me
OMe
O
H
NH2
NH2
2a
3
•
+
H
H
CH2Cl2
reflux
(2 equiv.)
N
Ph
N
N
(6.0 equiv)
a,b
b
1 week
Entry
R (substrate)
Product
Concd (M)
Yield
(%)
% ee
O
Me
y. 88%
(R)-Binaphthyldiamine
8
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Me (3a)
n-Pr (3b)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
0.2
0.2
0.2
0.4
0.4
0.2
0.2
0.6
0.4
0.4
0.2
0.2
0.2
0.2
99 (94)
94 (93)
91 (96)
73 (97)
63
8 (29)
50 (79)
84 (29)
98 (94)
99 (97)
98 (94)
98 (89)
96
98 (70)
39 (88)
98 (56)
97 (87)
97 (60)
79 (92)
86 (90)
50 (71)
—
(R)-BINUREA: (R)-10a
(7)
Ph(CH2)2 (3c)
BnOCH2 (3d)
CH2@CH(CH2)2 (3e)
CH3CH@CH (3f)
ClCH2 (3g)
iPr (3h)
Scheme 2. Synthesis of new axially chiral bis-urea ligands.
O
S
R
R
R
R
N
H
H
N
N
H
H
N
N
H
N
H
iBu (3i)
quant. (88)
90 (26)
H
N
H
N
Ph (3j)
CO2Me (3k)
CO2Ph (3l)
c
93 (93)
c
O
88 (quant.)
20 (93)
S
H (3m)
Cl (3n)
(R)-10b: R= Ph
(R)-11a: R= Ph
(R)-11b: R= benzyl
<10 (0)
(R)-10c: R= benzyl
(R)-10d: R= cumyl
Me
a
In all entries, the corresponding cyclohexene adduct 4 was obtained as a single
(R)-10e: R=
diastereomer.
1-naphthyl
b
c
In the parentheses, the optimized data of BINAMIDE are shown.
BF3ꢀOEt2 was used in the second step at ꢁ78 °C, instead of TFA.
Figure 1. Synthesized BINUREA derivatives and their thiourea analogues.

5654
S. Harada et al. / Tetrahedron Letters 50 (2009) 5652–5655
reaction of dienophiles with branched alkyl chains 3h and 3i, and
aromatic 3j, for which the Yb(III)/BINAMIDE 1a system was not
effective (yield 29–88%; 56–87% ee), was dramatically optimized
(entries 8–10). Every reaction took place efficiently in good to
excellent yields (84%-quantitative yield) with a high level of
enantioselectivity (97–98% ee). Concentrated reaction conditions
shortened the reaction time without a loss of selectivity. Substrates
with methoxy- (3k) and phenoxycarbonyl (3l) groups could also be
used in this catalyst system, although the ees were slightly de-
creased (entries 11 and 12). In the case of acryloyl-type dienophile
3m, the desired adduct was obtained in only 20% yield because the
dimerization and oligomerization of 3m were the predominant
reactions. The reaction with chlorine-substituted dienophile 3n
also suffered from side reactions, and the reaction mixture turned
black as the reaction proceeded.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Re-
search on Priority Areas ‘Advanced Molecular Transformations of
Carbon Resources’ and a Grant-in-Aid for Young Scientists (B) from
JSPS and the Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
References and notes
1. For recent reviews, see: (a) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299; (b)
Connon, S. J. Chem. Eur. J. 2006, 12, 5418; (c) Connon, S. J. Chem. Commun. 2008,
2499.
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recent reviews, see: (b) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed.
2008, 47, 1560.
These reaction products can be readily converted into stereose-
lectively substituted cyclohexenes or cyclohexenones in high
yields according to methods established by our group.10
In summary, we have developed axially chiral BINUREA 10 as a
new bis-urea ligand, which can be synthesized in a single opera-
tion from commercially available compounds. Yb(OTf)3/BINUREA
complex catalyzed the asymmetric Diels–Alder reactions of Dani-
shefsky-type diene and electron-deficient olefins to give highly
substituted cyclohexenes in optically active form. With BINUREA
and BINAMIDE in hand, the Diels–Alder reaction can be applicable
to a wide range of substrates. Further studies on this new catalyst
system of BINUREA with other metals, and its application to differ-
ent types of reactions, are now underway.
5. DMPU is
a representative example. This cyclic urea is often used as an
alternative to carcinogenic HMPA. Mukhopadhyay, T.; Seebach, D. Helv. Chim.
Acta 1982, 65, 385.
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2. Experimental
7. Metal/urea complexes have been extensively investigated. For selected
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E.; Larsen, E. Inorg. Chem. 2007, 46, 5166; (g) Yoo, H.; Mirkin, C. A.; DiPasquale,
A. G.; Rheingold, A. L.; Stern, C. L. Inorg. Chem. 2008, 47, 9727; (h) Shook, R. L.;
Gunderson, W. A.; Greaves, J.; Ziller, J. W.; Hendrich, M. P.; Borovik, A. S. J. Am.
Chem. Soc. 2008, 130, 8888.
8. (a) Gamez, P.; Dunjic, B.; Fache, F.; Lemaire, M. J. Chem. Soc., Chem. Commun.
1994, 1417; (b) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4275; (c)
Gamez, P.; Dunjic, B.; Lemaire, M. J. Org. Chem. 1996, 61, 5196; (d) Touchard, F.;
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F.; Bernard, M.; Fache, F.; Delbecq, F.; Guiral, V.; Sautet, P.; Lemaire, M. J.
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Fettinger, J. C.; Zavalij, P. Y.; Colyer, J. T.; Timmons, D. J.; Carducci, M. D. J. Org.
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amount of metal, see: (i) Hernández-Rodríguez, M.; Gabriela Avila-Ortiz, C.; del
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D. J. J. Am. Chem. Soc. 2009, 131, 9140.
2.1. General procedure for the Diels–Alder reaction of Yb(III)/
BINUREA complex (2a and 3a to 5a via 4a)
Yb(OTf)3 (18.6 mg, 30.0
lmol) and BINUREA (R)-10a (17.4 mg,
30.0 mol) taken in a test tube with a stirring bar were heated at
l
120 °C under reduced pressure (<0.1 mmHg) for 30 min. After
being allowed to cool to room temperature, the test tube was
charged with dry argon. Dichloromethane (CH2Cl2) (1.0 mL) and
DBU (9.0 lL, 60.0 lmol) were added successively, and the resulting
solution was stirred for 2 h at room temperature. The reaction ves-
sel was cooled to 0 °C and a solution of dienophile 3a (46.6 mg,
0.30 mmol) in CH2Cl2 (0.50 mL) was added, followed by the addi-
tion of diene 2a (150 lL, 0.60 mmol). The mixture was stirred for
3 h at the same temperature, and water (5.0 mL) was then added.
Insoluble materials were filtered through a pad of CeliteÒ. The
water layer was extracted three times with CH2Cl2, and the com-
bined organic layers were washed with brine and dried over
Na2SO4. After the volatile materials were removed under reduced
pressure, diastereoselectivity was checked by 1H NMR (a single
diastereomer). The crude product could be purified by column
chromatography (SiO2, hexane/AcOEt = 5/1) to give 4a as a color-
less oil, which was solidified upon standing.
The resulting crude mixture 4a was dissolved in CH2Cl2
(3.0 mL), and TFA (0.3 mL) was added at 0 °C. After being stirred
for 10 min at room temperature, the reaction was quenched by
the addition of aqueous saturated NaHCO3. The mixture was ex-
tracted three times with CH2Cl2, and the combined organic layers
were washed with brine and dried over Na2SO4. After the volatile
materials were removed under reduced pressure, the resulting res-
idue was purified by column chromatography (SiO2, hexane/
AcOEt = 1/1) to give 5a (66.5 mg, yield 99%) as a colorless solid.
The enantiomeric excess was determined to be 98% ee by HPLC
analysis (Daicel Chiralcel OJ-H, hexane/iPrOH = 65/35, f: 1.0 mL/
min, 254 nm, 23.9 min (minor), 29.8 min (major)).
9. Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807.
10. Sudo, Y.; Shirasaki, D.; Harada, S.; Nishida, A. J. Am. Chem. Soc. 2008, 130, 12588.
11. For examples of asymmetric Diels–Alder reactions using ketone-derived siloxy
dienes, see: (a) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2000, 122,
7843; (b) Thadani, A. N.; Stankovic, A. R.; Rawal, V. H. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5846; (c) Usuda, H.; Kuramochi, A.; Kanai, M.; Shibasaki, M. Org. Lett.
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(e) Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 1498; (f) Ward, D. E.;
Shen, J. Org. Lett. 2007, 9, 2843; See also: (g) Yamatsugu, K.; Yin, L.; Kamijo, S.;
Kimura, Y.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, 1070.
12. Asymmetric hetero-Diels–Alder reactions are well known. (a) Jørgensen, K. A.
Angew. Chem., Int. Ed. 2000, 39, 3558; For aldehydes and ketones, see a review:
(b) Pellissier, H. Tetrahedron 2009, 65, 2839; For imines, see reviews: (c)
Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099; (d) Rowland, G. B.;
Rowland, E. B.; Zhang, Q.; Antilla, J. C. Curr. Org. Chem. 2006, 10, 981.
13. (a) Inokuchi, T.; Okano, M.; Miyamoto, T.; Madon, H. B.; Takagi, M. Synlett 2000,
1549; (b) Inokuchi, T.; Okano, M.; Miyamoto, T. J. Org. Chem. 2001, 66, 8059.
14. Nishida, A.; Yamanaka, M.; Nakagawa, M. Tetrahedron Lett. 1999, 40, 1555. See
also Ref. 10. By the addition of tertiary amine, DA adducts can be isolated as 4,
and the excess diene remained unchanged during the reaction as well. Without
amines, DA adducts were directly converted to 5.

S. Harada et al. / Tetrahedron Letters 50 (2009) 5652–5655
5655
15. We did not obtain reproducible results regarding the optical resolution of 6
following the reported method: (a) Dethloff, W.; Mix, H. Chem. Ber. 1949, 534;
A similar problem has been reported previously: (b) Gillespie, K. M.; Sanders, C.
J.; O’Shaughnessy, P.; Westmoreland, I.; Thickitt, C. P.; Scott, P. J. Org. Chem.
2002, 67, 3450.
configuration of 9 synthesized from ( )-6 was determined by comparison
to the spectral data of 9 synthesized from purchased optically pure 6.
18. For these optimized conditions with (S)-10a (10 mol %): 7% yield; –76% ee. (S)-
10a was still mismatched ligand.
19. Without this operation, we did not obtain reproducible results. A precise
mechanistic investigation is now underway.
20. For the reaction of 2a and 3a, (R)-10c has similar reactivity and selectivity to
(R)-10a. But, for 2a and 3h, (R)-10c gave only 12% yield and 84% ee (0.6 M, 0 °C,
3 h).
16. For the synthesis of racemic 6, see Ref. 15. See also: Marxen, T. L.; Johnson, B. J.;
Nilsson, P. V.; Pignolet, L. H. Inorg. Chem. 1984, 23, 4663.
17. Recently, both isomers of optically active 6,60-dimethyl-2,20-biphenyldiamine
(6) have become commercially available from Aldrich. The absolute