α,β-Divinyl tetrahydropyrroles as chiral chain diene ligands in rhodium(I)-catalyzed enantioselective conjugated additions

Article abstract of DOI:10.1021/ol103152t

A series of α,β-divinyl tetrahydropyrroles, synthesized by asymmetric allylic C-H bond activation/conjugated diene addition reaction of ene-2-dienes, were found to be very efficient chiral chain diene ligands in the rhodium-catalyzed conjugated addition of organoboronic acids to various α,β-unsaturated compounds, achieving the desired chiral adducts with good to excellent yields and ee values.(Figure Presented)

Full text of DOI:10.1021/ol103152t

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1122–1125
r,β-Divinyl Tetrahydropyrroles as Chiral
Chain Diene Ligands in Rhodium(I)-
Catalyzed Enantioselective Conjugated
Additions
Qian Li, Zhe Dong, and Zhi-Xiang Yu*
Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of
Bioorganic Chemistry and Molecular Engineering, College of Chemistry, Peking
University, Beijing, 100871, China
yuzx@pku.edu.cn
Received December 27, 2010
ABSTRACT
A series of R,β-divinyl tetrahydropyrroles, synthesized by asymmetric allylic C-H bond activation/conjugated diene addition reaction of ene-2-
dienes, were found to be very efficient chiral chain diene ligands in the rhodium-catalyzed conjugated addition of organoboronic acids to various
R,β-unsaturated compounds, achieving the desired chiral adducts with good to excellent yields and ee values.
Since the pioneering studies by the groups of Hayashi
and Carreira, chiral cyclic dienes have now emerged as a
novel class of highly effective steering ligands in transition
metal-catalyzed enantioselective synthesis (Figure 1).1-5
Accordingly, ever increasing enantioselective reactions can
be catalyzed by transition metal-diene complexes.6,7 Par-
ticularly noteworthy is that in some cases chiral dienes are
even more advantageous than other types of ligands in
achieving challenging asymmetric reactions. To increase
the practicability and versatility ofthese novelligands, easy
and straightforward synthetic accesses to these dienes are
of prime importance and continuous endeavors in this line
are ongoing in many research groups.
(1) (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am.
Chem. Soc. 2003, 125, 11508. (b) Fischer, C.; Defieber, C.; Suzuki, T.;
Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 1628.
(4) For leading references on phosphine-alkene hybrid ligands, see:
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(a) Maire, P.; Deblon, S.; Breher, F.; Geier, J.; Bohler, C.; Ruegger, H.;
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€
Schonberg, H.; Grutzmacher, H. Chem.;Eur. J. 2004, 10, 4198.
(b) Shintani, R.; Duan, W.-L.; Nagano, T.; Okada, A.; Hayashi, T.
Angew. Chem., Int. Ed. 2005, 44, 4611. (c) Duan, W.-L.; Iwamura, H.;
Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2007, 129, 2130.
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Chem., Int. Ed. 2007, 46, 3139. (e) Stemmler, R. T.; Bolm, C. Synlett
2007, 9, 1365. (f) Minuth, T.; Boysen, M. M. K. Org. Lett. 2009, 11, 4212.
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Chem., Int. Ed. 2004, 43, 3364. (b) Johnson, J. B.; Rovis, T. Angew.
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Chem., Int. Ed. 2008, 47, 840. (c) Defieber, C.; Grutzmacher, H.;
Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4482. (d) Shintani,
R.; Hayashi, T. Aldrichim. Acta 2009, 42, 31.
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N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T.
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Stephenson, C. R. J.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127,
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2006, 128, 5628. (g) Aikawa, K.; Akutagawa, S.; Mikami, K. J. Am.
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F. Angew. Chem., Int. Ed. 2010, 49, 1143.
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Wang, Z.-Q.; Shao, C.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008, 10, 4101.
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r
10.1021/ol103152t
Published on Web 02/10/2011
2011 American Chemical Society

Scheme 1. Rhodium-Catalyzed Allylic C-H Activation/Addi-
tion to Conjugated Diene
Scheme 2. Conjugated Addition of Phenylboronic Acid to
2-Cyclohexenone, Using 1a
Figure 1. Examples of chiral diene ligands.
In addition to trying to design novel routes to easy
synthesis of chiral cyclic dienes, which are the first genera-
tion of the widely used chiral diene ligands, scientists also
tested whether acyclic dienes, which are usually much easier
to access, can also function as efficient diene ligands for
the asymmetric catalysis. Du and co-workers have found a
family offlexiblechiral chaindienes (7,8,and9,seeFigure1)
that can achieve up to 85% ee in Rh-catalyzed conjugated
addition reactions.8 This demonstrated the possibility of
using flexible chiral chain dienes in the asymmetric catalysis.
The low asymmetric induction in Du’s ligands could be due
to the facts that acyclic dienes are very flexible in geometry
and have many orientations in coordination to the metal
center in catalysis. Continuous efforts are required to
develop other chiral acyclic diene ligands that can achieve
high asymmetric inductions as chiral cyclic dienes do.
Recently, we reported a highly enantioselective Rh-cata-
lyzed allylic C-H activation/addition to conjugated dienes
using ene-2-dienes as substrates to synthesize multifunctional
R,β-divinyl tetrahydropyrroles, tetrahydrofurans, and cyclo-
pentanes (Scheme 1).9a,b Asymmetric synthesis of two adja-
cent sp3 carbon centers with one quaternary carbon in a series
of R,β-divinyl tetrahydropyrrole, tetrahydrofuran, and cyclo-
pentane structures was also achieved by us (Scheme 1).9c We
are currently trying to apply this reaction and its products to
synthesis. Inspired by the chemistry of diene ligands, we
decided to test whether these R,β-divinyl tetrahydropyrroles
could also act as chiral chain diene ligands for transition
metal-catalyzed enantioselective reactions.
Our first attempt was to test whether R,β-divinyl tetra-
hydropyrroles can act as chiral chain dienes in Rh-cata-
lyzed conjugated addition of organoboronic acids to
2-cyclohexenone (Scheme 2).10 To our delight, our chiral
chain diene ligand 1a (which was directly obtained by the
reaction shown in Scheme 1 and was 94% in ee) can give
89% yield and 91% ee (this equals a retained 97% ee, if a
pure chiral ligand could be used)11 in the conjugated addition
of phenyl boronic acid to 2-cyclohexenone at room tempera-
ture in 2 h. During the course of our work, Du and co-
workers realized up to 96% ee in similar reactions using diene
10 (Figure 1).8e Therefore, our and Du’s results clearly show
that chiral chain dienes are competitive with chiral cyclic
dienes as ligands in rhodium-catalyzed conjugated additions
of organoboronic acids to the R,β-unsaturated compounds.
(7) For leading references on expanding the application of chiral
olefin ligands in asymmetric catalysis, see: (a) Nishimura, T.; Kumamoto,
H.; Nagaosa, N.; Hayashi, T. Chem. Commun. 2009, 5713.
(b) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.; Hayashi,
T. J. Am. Chem. Soc. 2009, 131, 13588. (c) Gendrineau, T.; Genet, J.-P.;
Darses, S. Org. Lett. 2010, 12, 308. (d) Nishimura, T.; Wang, J.;
Nagaosa, M.; Okamoto, K.; Shintani, R.; Kwong, F.; Yu, W.; Chan,
A. S. C.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 464. (e) Nishimura,
T.; Kawamoto, T.; Nagaosa, M.; Kumanmoto, H.; Hayashi, T. Angew.
Chem., Int. Ed. 2010, 49, 1638. (f) Shintani, R.; Isobe, S.; Takeda, M.;
Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 3795. (g) Shintani, R.;
Takeda, M.; Nishimura, T.; Hayashi, T. Angew. Chem., Int. Ed. 2010, 49,
3969. (h) Wang, Z.-Q.; Feng, C.-G.; Zhang, S.-S.; Xu, M.-H.; Lin, G.-Q.
Angew. Chem., Int. Ed. 2010, 49, 5780. (i) Nishimura, T.; Maeda, Y.;
Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 7324. (j) Nishimura, T.;
Yasuhara, Y.; Sawano, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132,
7872. (k) Nishimura, T.; Makino, H.; Nagaosa, M.; Hayashi, T. J. Am.
Chem. Soc. 2010, 132, 12865. (l) Shintani, R.; Takeda, M.; Tsuji, T.;
Hayashi, T. J. Am. Chem. Soc. 2010, 132, 13168. (m) Pattison, G.;
Piraux, G.; Lam, H. W. J. Am. Chem. Soc. 2010, 132, 14373. (n) Shintani,
R.; Hayashi, T. Org. Lett. 2010, 13, 350.
(8) (a) Hu, X.; Zhuang, M.; Cao, Z.; Du, H. Org. Lett. 2009, 11, 4744.
(b) Hu, X.; Cao, Z.; Liu, Z.; Wang, Y.; Du, H. Adv. Synth. Catal. 2010,
352, 651. (c) Cao, Z.; Du, H. Org. Lett. 2010, 12, 2602. For a reference on
terminal-alkene phosphine hybrid ligand, see: (d) Liu, Z.; Du, H. Org.
Lett. 2010, 12, 3054. (e) Wang, Y; Hu, X.; Du, H. Org. Lett. 2010, 12, 5482.
(9) For the racemic reaction, see: (a) Li, Q.; Yu, Z.-X. J. Am. Chem.
Soc. 2010, 132, 4542. Addition and correction: (b) Li, Q.; Yu, Z.-X.
J. Am. Chem. Soc. 2010, 132, 6862. For the asymmetric version, see: (c)
Li, Q.; Yu, Z.-X. Angew. Chem., Int. Ed. 2011. DOI: anie.201005215.
(10) For leading reviews on Rh-catalyzed asymmetric conjugated
additions, see: (a) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103,
2829. (b) Gennari, C.; Monti, C.; Piarulli, U. Pure Appl. Chem. 2006, 78,
€
303. (c) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis
2007, 1279. (d) Edwards, H. J.; Hargrave, J. D.; Penrose, S. D.; Frost,
C. G. Chem. Soc. Rev. 2010, 39, 2093.
(11) As one referee required that at least one reaction should be tested
using the enantiomeric pure diene ligand, we carried out a standard
reaction shown in Table 1 using diene ligand 1a in 100% ee, which was
obtained by preparative HPLC (Chiralpak OD column). In this case,
97% ee was obtained (see entry 9, Table 1, and the study of nonlinear
effect part of the Supporting Information).
Org. Lett., Vol. 13, No. 5, 2011
1123

A great advantage of our allylic C-H activation/diene
addition is that a series of acyclic dienes can be readily
synthesized with very good enantioselectivity so that they
can be tested as chiral chain diene ligands in transition
metal-catalyzed conjugated addition. Therefore, besides chiral
diene 1a, we also tested other chiral dienes to see if better
results could be achieved in the present Rh-catalyzed
conjugated addition of organoboronic acid to 2-cyclohex-
enone (Scheme 3). It was found that different alkyl sub-
stituents at the internal position of the alkene of the ligands
(1b, 1c, and 1d) did not influence the ee obviously. When a
terminal substituent was introduced to the alkene of the
ligands (1e and 1g), only a trace amount of product could be
obtained in these reactions, presumably due to the steric
hindrance in the ligands that prevents the effective coordina-
tion of the diene to the rhodium center. Besides, the scaffold
of these ligands is also important for achieving high ee, as the
ligand 1f with the diene motif one more carbon away from
the N atom than that in 1d gave a sharply decreased ee.
Diene 1a is not a good solid and it is difficult for us to
further improve its enantiopurity by recrystallization. There-
fore, optimizing other reaction conditions was carried out to
achieve higher ee of the target reaction by using 1a (94% in
enantiomeric excess).11 We found that lowering the reaction
temperature resulted in a decreased reaction yield, although
the ee was slightly improved by 1% (Table 1, entry 2). We
also tested the catalytic reaction using different rhodium
loadings. The reaction yields were decreased without erosion
of ee when less than 2.5 mol % of [Rh(coe)2Cl]2 was used
(entries 3 and 4). However, further increasing the rhodium
loading gave no better yield and ee (entriy 5). Besides, the
ratio of water is important to achieve high yield and ee
(entries 1, 6, and 7). When the ratio of water was decreased, a
low yield and lower ee were obtained. This indicates that
water is responsible for the acceleration of this catalytic
reaction. When the ratio of water was increased, the yield
was improved with a slightly decreased ee. We also tested the
solvent effect by using methanol instead of water (entry 8). It
was shown that water is especially vital to obtain a high ee in
this reaction. Finally, we chose 2.5 mol % of [Rh(coe)2Cl]2,
6.0 mol % of 1a (with 94 ee%),11 dioxane/H2O (v/v, 2/1),
and room temperature as the optimal reaction conditions to
further study the scope of this asymmetric reaction.
Scheme 3. Screening of the Chiral Chain Dienes (the addition
products ee values in parentheses are the retained ee values)
We were pleased to find that the rhodium-catalyzed
conjugated addition under the optimal reaction conditions
proceeded smoothly in 2 h to give a variety of chiral adducts
in 55-93% yields, and 85-91% ee’s (90-98% ee’s were
retained). Various para- and meta-substituted aryl boronic
acids afforded the corresponding chiral adducts in good to
excellent yields and ee values (Table 2). In this transforma-
tion, ester and ketone, as well as hydroxyl groups can be
tolerated without any erosion in ee (entries 6-8). Notably,
Table 1. Optimization of Reaction Conditionsa
entry
[Rh(coe)2CI]2 (mol %)
solvent
temp
yield b (%)
eec (%)
ee retained (%)
1
2
3
4
5
6
7
8
9d
2.5
2.5
1.0
1.5
3.5
2.5
2.5
2.5
2.5
dioxane/H2O (v/v, 2/1)
dioxane/H2O (v/v, 2/1)
dioxane/H2O (v/v, 2/1)
dioxane/H2O (v/v, 2/1)
dioxane/H2O (v/v, 2/1)
dioxane/H2O (v/v, 10/1)
dioxane/H2O (v/v, 1/3)
dioxane/MeOH (v/v, 2/1)
dioxane/H2O (v/v, 2/1)
rt
89
61
70
79
90
42
95
91
89
91
92
90
91
90
89
88
88
97
97
98
96
97
96
95
94
94
0 °C
rt
rt
rt
rt
rt
rt
rt
a 10 mol % of KOH was used, which was added to the reaction system as a 0.075 M solution. b Isolated yield. c Ee was determined by HPLC
(Chiralpak AD-H column). d The enantiomerically pure diene ligand obtained by preparative HPLC (Chiralpak OD column) was used (see ref 11).
1124
Org. Lett., Vol. 13, No. 5, 2011

Table 2. Scope of the Asymmetric Conjugated Additions
Scheme 4. Unsuccessful Reactions
our ligands. The ortho-substituted arylboronic acid (entry
11) and naphthalen-1-ylboronic acid (entry 12) can partici-
pate in this reaction and gave the desired products in
excellent ee values, which were superior to the results
obtained by Du’s chiral chain ligands. Besides 2-cyclohex-
enone, the conjugated additions to 2-cyclopentenone, 2-
cycloheptenone, and 5,6-dihydro-2H-pyran-2-one (entries
17-19) were also tested, showing that the ee values of these
reactions were 88%, 85%, and 92% (94%, 90%, and 98%
retained), respectively. We also studied the nonlinear effect
of the conjugated addition of phenylboronic acid to 2-
cyclohexenone. It turned out that there is no nonlinear effect
in this reaction, suggesting that there is one chiral diene ligand
coordinated to the rhodium center in the stereo-determining
step (see the Supporting Information for details).
Unfortunately, for some of the electron-deficient aryl
boronic acids, our ligand cannot give reasonable yields
(Scheme 4). Besides, the addition of phenylboronic acids
to furan-2(5H)-one, the acyclic R,β-unsaturated ester, and
ketone only yield trace products, respectively (Scheme 4).
In summary, we have reported a new family of chiral chain
dienes, synthesized by asymmetric allylic C-H activation/
addition reaction, as effective steering ligands for the con-
jugated addition of organoboronic acids to R,β-unsaturated
compounds. These results highlight the synthetic utility of
products obtained by the asymmetric C-H activation meth-
odology. These substituted tetrahydropyrroles are not only
useful structural motifs in organic synthesis, but are also
applicable to the transition metal-catalyzed asymmetric reac-
tions as a new class of diene ligands. Further application of
these chiral chain diene ligands in other asymmetric reactions
and understanding the coordination mode as well as the origin
of the chiral induction are under investigation in our group.
Acknowledgment. We thank the National Natural
Science Foundation of China (20825205-National Science
Fund for Distinguished Young Scholars, 20772007,
20672005) and the Ministry of Science and Technology
(2011CB808600 and 2010CB833203-National Basic Re-
search Programs of China-973 Programs) for financial
support. We also thank Prof. Haifeng Du at the Institute
of Chemistry, the Chinese Academy of Sciences for the
help of HPLC analysis of 3-phenylcyclopentanone.
a The diene ligand 1a used in these reactions is in 94% ee. b The
absolute configuration was determined by comparing the optical rota-
tion with the reported one or by analogy. c Isolated yield. d The ee was
determined by chiral HPLC (Chiralpak AD-H, AS-H, OB-H, OD-H,
OJ-H columns were used as indicated in the Supporing Information).
when the arylboronic acid bearing a hydroxymethyl group
at the para-position was used, the highest ee in this catalytic
reaction was obtained (entry 6). The catalytic conjugated
addition reaction is not sensitive to the steric effects using
Supporting Information Available. Experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 5, 2011
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