Highly enantioselective relay catalysis in the three-component reaction for direct construction of structurally complex heterocycles

Article abstract of DOI:10.1021/ol1006086

A highly enantioselective three-component cascade reaction, consisting of an enantioselective [4+2] cycloaddition reaction catalyzed by chiral phosphoric acid and a subsequent catalytic intramolecular hydroamination by gold(I) complex, provides a unique method to access structurally diverse julolidine derivatives in high optical purity.

Full text of DOI:10.1021/ol1006086

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2266-2269
Highly Enantioselective Relay Catalysis
in the Three-Component Reaction for
Direct Construction of Structurally
Complex Heterocycles
Chao Wang, Zhi-Yong Han, Hong-Wen Luo, and Liu-Zhu Gong*
Hefei National Laboratory for Physical Sciences at the Microscale and Department of
Chemistry, UniVersity of Science and Technology of China, Hefei, 230026, China
gonglz@ustc.edu.cn
Received March 16, 2010
ABSTRACT
A highly enantioselective three-component cascade reaction, consisting of an enantioselective [4+2] cycloaddition reaction catalyzed by
chiral phosphoric acid and a subsequent catalytic intramolecular hydroamination by gold(I) complex, provides a unique method to access
structurally diverse julolidine derivatives in high optical purity.
Conventional wisdom implies that asymmetric reactions
known so far are dominantly mediated by a single type of
catalyst such as either a metal-based or an organocatalyst.1
The organic/metallic binary catalyst systems that are com-
prised of two fundamentally different catalysts that operate
cooperatively or sequentially in the same reaction solution,
now known as cooperative catalysis and relay catalysis (or
cascade catalysis), hold great potential in the creation of new
transformations where each type of catalyst failed to afford
alone.2 Particularly, recent elegant advances have cor-
roborated the high ability of this concept to establish new
asymmetric catalytic reactions.3 In addition to the funda-
mental significance, the related reactions have some practical
advantages such as maximizing the operative efficiency,
essential avoidance of an additional workup process, and
reducing relevant pollution associated with stepwise catalytic
protocols.
(3) (a) Chen, G.; Deng, Y.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi,
M. C. K.; Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12, 1567. (b)
Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. Org. Lett. 2001, 3,
3329. (c) Kanayama, T.; Yoshida, K.; Miyabe, H.; Takemoto, Y. Angew.
Chem, Int. Ed. 2003, 42, 2054. (d) Mukherjee, S.; List, B. J. Am. Chem.
Soc. 2007, 129, 11336. (e) Komanduri, V.; Krische, M. J. J. Am. Chem.
Soc. 2006, 128, 16448. (f) Chercheja, S.; Eilbracht, P. AdV. Synth. Catal.
2007, 349, 1897. (g) Rueping, M.; Antonchick, A. P.; Brinkmann, C. Angew.
Chem., Int. Ed. 2007, 46, 6903. (h) Hu, W.-H.; Xu, X.-F.; Zhou, J.; Liu,
W.-J.; Huang, H.-X.; Hu, J.; Yang, L.-P.; Gong, L.-Z. J. Am. Chem. Soc.
2008, 130, 7782. (i) Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2008,
130, 14452. (j) Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer,
R. I.; Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 10796. (k)
Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J. J. Am.
Chem. Soc. 2009, 131, 9140. (l) Belot, S.; Vogt, K. A.; Besnard, C.; Krause,
N.; Alexakis, A. Angew. Chem., Int. Ed. 2009, 48, 8923. (m) Terada, M.;
Toda, Y. J. Am. Chem. Soc. 2009, 131, 6354. (n) Cai, Q.; Zhao, Z.-A.;
You, S.-L. Angew. Chem., Int. Ed. 2009, 48, 7428. (o) Hashmi, A. S. K.;
Hubbert, C. Angew. Chem., Int. Ed. 2010, 49, 1010. (p) de Armas, P.;
Tejedor, D.; Garc´ıa-Tellado, F. Angew. Chem., Int. Ed. 2010, 49, 1013.
(1) (a) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. ComprehensiVe
Asymmetric Catalysis; Springer: New York, 1999. (b) Caprio, V.; Williams,
J. M. J. Catalysis in Asymmetric Synthesis; Wiley VCH: Chichester, U.K.,
2009. (c) Berkessel, A.; Groger, H. Asymmetric Organocatalysis, (Wiley
VCH: Weiheim, Germany , 2005.
(2) (a) Shao, Z.; Zhang, H. Chem. Soc. ReV. 2009, 38, 2745. (b) Zhou,
J. Chem. Asian J. 2010, 5, 422.
10.1021/ol1006086  2010 American Chemical Society
Published on Web 04/21/2010

The direct generation of chiral molecules with structural
complexity and diversity from simple substrates with high
levels of stereochemical control constitutes an important, but
still a formidable challenge in organic chemistry. Asymmetric
multicomponent reactions provide an important tool to obtain
this target.4 The relay catalysis (or cascade catalysis) holds
great potential, but has been recognized much less in the
development of new multicomponent reactions for the
stereoselective construction of structurally complex and
diverse chiral heterocyclic architectures. Herein, we will
report an asymmetric relay catalytic three-component reaction
that consists of a sequential [4+2] cycloaddition and in-
tramolecular hydroamination under the relay catalysis of a
chiral Brønsted acid and achiral gold complex, highly
yielding structurally complex julolidine derivatives, an
important structural motif found in either biologically
interesting substances5 or organic materials,6 with excellent
levels of stereoselectivity.
catalyst for the second annulation between secondary amine
and carbon-carbon triple bond in view of the substrate-
sensitive gold-catalyzed hydroaminations.8,9
The viability of the sequential reaction was first attempted
by a reaction of 1a, 4-bromobenzaldehyde 2a, and an
enamide 3 under the influence of a binary catalyst system
comprised of 15 mol % of phosphoric acid 5 (Figure 1) and
Figure 1. The Brønsted acid and phosphorus ligands used in this
study.
Very recently, highly enantioselective Povarov reactions
have been established by using binol-based phosphoric acid
catalysts.7 We and Che have demonstrated that the gold
complexes and Brønsted acids can compatibly work in the
relay catalysis for the consecutive hydroamination/transfer
hydrogenation of alkynes, yielding chiral amines in excellent
levels of enantioselectivity.8 Inspired by these achievements,
we proposed that a cascade reaction for the enantioselective
direct generation of julolidine derivatives 4 might be able
to commence with a Brønsted acid-catalyzed three-compo-
nent inverse electron-demand aza-Diels-Alder reaction
(Povarov reaction)7a of a 2-(2-propynyl)aniline derivative (1),
aldehyde, and enamide, presumably producing an intermedi-
ate II, which should principally undergo a subsequent
hydroamination reaction under the catalysis of an appropriate
gold complex to give 4 via an active intermediate III
(Scheme 1). Even though the related works have been
10 mol % of (Ph3P)AuMe.8a The reaction was conducted at
-40 °C for 12 h and then at room temperature for 24 h. To
our delight, the desired reaction occurred to give the
predictable product 4a, which was, however, too unstable
to be isolated and thereby was immediately reduced with
acetic acid and sodium triacetoxyborohydride,10 leading to
the generation of 6a and its diastereomer in a total 30% yield
with 98% ee for each diastereomer (Table 1, entry 1), but
Table 1. Screening Gold Complexes and Optimization of
Reaction Conditionsa
B*-H
time yield of
ee
entry
Au(I) (mol %)
(mol %) solvent (h)b 6a (%)c e (%)d e
,
,
Scheme 1. General Concept for the Synthesis of Julolidines
Derivatives by Cascade Reactions under the Relay Catalysis of
Chiral Brønsted Acid and Gold Complex
1
2
3
4
5
6
7
8
(Ph3P)AuMe(10)
(L1)AuMe(10)
(L2)AuMe(10)
(L2)AuMe(10)
(L2)AuMe(10)
(L2)AuMe(5)
15
15
15
15
15
15
10
10
PhCH3 24
PhCH3 24
PhCH3 24
CH2Cl2 12
CHCl3 12
CH2Cl2 12
CH2Cl2 12
26(4)
53(9)
44(31) 97(98)
63(11) 97(96)
38(9)
51(5)
57(9)
98(98)
96(98)
85(72)
97(94)
95(96)
(L2)AuMe(10)
(Ph3P)AuNTf2(10)
CH2Cl2
4
47(26) 94(95)
a The reaction of aniline 1a (0.1 mmol), 4-bromobenzaldehyde (0.105
mmol), and 3 (0.3 mmol) was carried out at -40 °C for 12 h and room
temperature for the indicated time, in the presence of 3 Å MS, phosphoric
acid 5, and an Au(I) complex as indicated. b The time refers to the
hydroamination step at room temperature. c Isolated yield. d Determined
by HPLC. e The data in parentheses are for the minor diastereomer of 6a.
available to provide some light for each individual step,7,8
we believed that the validation of the proposed cascade
reaction might still be the discovery of an efficient gold
still with an accompanying trace amount of uncyclized
Povarov product (IIa). Variation of the ligand from triph-
enylphosphine to 2-biphenylyldicyclohexylphosphine (L1)9a
coordinating to gold(I) led to a significant improvement in
the yield (62%) with excellent levels of enantioselectivity
for both diastereomers, and significantly, no Povarov product
(4) (a) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
(b) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46.
(5) Haidekker, M. A.; Ling, T.; Anglo, M.; Stevens, H. Y.; Frangos,
J. A.; Theodorakis, E. A. Chem. Biol. 2001, 8, 123.
(6) Yao, Y.-S.; Zhou, Q.-X.; Wang, X.-S.; Wang, Y.; Zhang, B.-W. J.
Mater. Chem. 2006, 16, 3512.
Org. Lett., Vol. 12, No. 10, 2010
2267

was detected (entry 2). A gold complex of 2-biphenylyldi-
tert-butylphosphine (L2)9a provided an even higher total yield
of 6a and its diastereomer (75%, entry 3). The reaction
conducted in dichloromethane not only maintained the yield
and stereoselectivity in comparison of that in toluene, but
also much favored the formation of 6a (entry 4). Tuning of
the reaction parameters including solvents and the stoichi-
ometry of gold complex and phosphoric acid 5 led to no
enhancement of the reaction performance (entries 5-7). The
Table 2. Generality of the Reactiona
yield (%)b d
ee (%)c d
,
,
entry
R1/R2/R3
H/Ph/Ph
6
9b
1
2
3
4
5
6
7
8
6b
6c
6d
6e
6f
6g
6h
6i
67(12)
70(15)
66(9)
92(92)
96(97)
92(92)
94(92)
97(97)
98(97)
99(98)
96(96)
97(96)
96(96)
93(-)
Ph3PAuNTf2 showed high catalytic activity, but resulted
H/Ph/4-ClC6H4
in a slightly lower enantioselectivity than other gold catalyst
partners of the Brønsted acid (entry 8). Screening different
phosphoric acids11 revealed that 3,3′-bis(9-anthracenyl)binol-
derived phosphoric acid 5 is the most suitable catalyst for
this sequential transformation, and notably, the 3,3′-bi(4-
chlorophenyl)binol-derived phosphoric acid that afforded
Povarov reaction in high stereoselectivity7a was unable to
give satisfactory results (Table S1, see the Supporting
Information).
We next investigated the generality of the protocol under
the optimized conditions (Table 2). Electronically poor,
neutral, or rich benzaldehydes were all able to participate in
the smooth relay catalytic three-component reaction, which
was treated with AcOH and NaBH(OAc)3 to furnish juloli-
dine derivatives in high yields and excellent levels of
enantioselectivity (entries 1-11). Interestingly, substitution
at either the para- or meta-position of the phenyl group was
well tolerable and able to afford high stereoselectivity.
Moreover, 2-furancarbaldehyde and an aliphatic aldehyde
could be operative in fairly good yields and excellent
enantioselectivity (entries 12 and 13). Variation of substi-
tutents bonded to either C-C triple bond or to the benzene
ring also underwent a clean reaction, giving the desired
products in high yields and with excellent enantioselectivity
(entries 14-16).
H/Ph/4-MeC6H4
H/Ph/4-MeOC6H4
H/Ph/4-CNC6H4
H/Ph/4-MeO2CC6H4
H/Ph/4-NO2C6H4
H/Ph/3-ClC6H4
61(7)
70(14)
72(11)
56(12)
63(6)
68(14)
62(11)
63(-)
64(11)
47(12)
61(16)
59(12)
62(20)
9
H/Ph/3-NO2C6H4
H/Ph/3-CF3C6H4
H/Ph/3-MeOC6H4
H/Ph/2-Furyl
H/Ph/PhCH2CH2
H/4-FC6H4/4-BrC6H4
H/2-Naph/4-BrC6H4
4-Cl/Ph/4-BrC6H4
6j
6k
6l
6m
6n
6o
6p
6q
10
11
12
13
14
15
16
92(90)
96(96)
97(96)
97(97)
>99(>99)
a The reaction of an aniline 1 (0.1 mmol), an aldehyde (0.105 mmol),
and 3 (0.3 mmol) was carried out at -40 °C for 12 h and room temperature
for 12 h, in the presence of 3 Å MS, 15% phosphoric acid 5, and 10%
(L2)AuMe. b Isolated yield. c Determined by HPLC. d The data in paren-
theses are for the minor diastereomer of 6.
Previous works demonstrated that methyl-gold complex
was able to react with some strong Brønsted acid to form
a chiral cationic gold(I) complex.13 To understand if the
cationic gold(I) or methyl-gold complex participated in
the catalysis, we performed 31PNMR spectrometric studies
on each gold catalyst species (Figure S1, SI). The 31PNMR
spectrum of a reaction mixture of (L2)AuMe shows a
signal at 69.16 ppm. The phosphoric acid 5 gives a NMR
peak at 0.55 ppm. The reaction mixture of (L2)AuMe and
5 with 1/1 ratio shows two new signals at 55.15 and 6.19
ppm, respectively, and the signals corresponding to
(L2)AuMe and 5 both disappeared. The gold phosphate 7
in situ generated from a reaction mixture of silver
phosphate complex with (L2)AuCl according to the
literature procedure14 showed two signals at 55.14 and
6.32 ppm, which are consistent with the signals assigned
to the product from reaction of (L2)AuMe with 5. Thus,
the methyl-gold complex reacts readily with phosphoric
acid to give the phosphates cleanly at room temperature
(Scheme 2).
X-ray crystallographic analysis was used to determine the
relative and absolute stereochemistry. The crystal structure12
of 6i shows that the Brønsted acid-catalyzed [4+2] cycload-
dition in the cascade reaction and reduction of the enamine
4 generated from the subsequent hydroamination are both
cis-selective and thereby (1S,3S,5R)-julolidine derivatives
were preferentially produced.
(7) (a) Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am.
Chem. Soc. 2009, 131, 4598. (b) Bergonzini, G.; Gramigna, L.; Mazzanti,
A.; Forchi., M.; Bernardi, L.; Ricci, A. Chem. Commun. 2010, 327. (c)
Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128, 13070.
(8) (a) Han, Z.-Y.; Xiao, H.; Chen, X.-H.; Gong, L.-Z. J. Am. Chem.
Soc. 2009, 131, 9182. (b) Liu, X.-Y.; Che, C.-M. Org. Lett. 2009, 11, 4204.
(9) (a) Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am. Chem.
Soc. 2005, 127, 6178. (b) Me´zailles, N.; Ricard, L.; Gagosz, F. Org. Lett.
2005, 7, 4133. (c) Hashimi, A. S. K. Chem. ReV. 2007, 107, 3180. (d) Li,
Z.; Brouwer, C.; He, C. Chem. ReV. 2008, 108, 3239.
(10) (a) Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini,
M. J. Org. Chem. 1994, 59, 5328. (b) Gribble, G. W.; Nutaitis, C. F. Org.
Prep. Proc. Int. 1985, 17, 317.
Scheme 2. The Reaction of (L2)AuMe and Phosphoric Acid 5
(11) (a) Akiyama, T. Chem. ReV. 2007, 107, 5744. (b) Terada, M. Chem.
Commun. 2008, 4097. (c) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007,
107, 5713.
(12) CCDC 763776. See the Supporting Information for details. The
crystallographic coordinates have been deposited with the Cambridge
Crystallographic Data Centre; deposition no. 763776. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre,
12 Union Rd., Cambridge CB2 1EZ, UK or via www.ccdc.cam.ac.uk/conts/
retrieving.html.
2268
Org. Lett., Vol. 12, No. 10, 2010

This relay catalytic reaction was believed to first undergo
a Brønsted acid-catalyzed [4+2] cycloaddition reaction and
a subsequent intramolecular hydramination reaction catalyzed
by a gold complex. However, previous reports revealed that
gold complexes serve as good Lewis acids capable of
catalyzing asymmetric reactions.15 To figure out if the gold
complexes participated in accelerating the [4+2] reaction,
we performed a control reaction of 1a and 4-bromobenzal-
dehyde (2a) with enamide 3 in the presence of 10 mol % of
the chiral gold phosphate 7 in situ generated from silver
phosphate and (L2)AuCl (Figure S2, SI). However, the aza-
Diels-Alder reaction was not observed by 1HNMR, indicat-
ing that the gold complex used in this case is unable to
catalyze the aza-Diels-Alder reaction (see the SI), instead
the phosphoric acid served as the real catalyst of the first
step. On the contrary, we have found that the cascade reaction
occurred smoothly in the presence of 10 mol % of (L2)AuMe
and 5 (Table 1, entry 7), indicating that the methyl-gold
complex is difficult to completely convert into gold phos-
phate at -40 °C, otherwise the Povarov reaction would have
not taken place as demonstrated by the control reaction.
Instead, (L2)AuMe can be rapidly transformed into gold
phosphate 7 with 5 at room temperature as shown by
31PNMR spectra (Scheme 2 and Figure S1, SI), which served
as the catalyst of intramolecular hydroamination.
Figure 2. Kinetic studies on the hydroamination reaction of IIa
by different gold complexes: (2) the (L2)AuMe catalyzed reaction;
(9) the reaction catalyzed by 10 mol % of 7; (b) the reaction
catalyzed by 10 mol % of 7 and 5.
also assists the gold complex to catalyze the subsequent
hydroamination reaction.
In summary, we have presented a highly enantioselective
three-component cascade reaction, consisting of an enanti-
oselective [4+2] cycloaddition reaction catalyzed by chiral
phosphoric acid and a subsequent catalytic intramolecular
hydroamination by a gold(I) complex, providing a unique
method for the preparation of structurally diverse and
complex julolidine derivatives in high optical purity. Kinetic
studies reveal that the Brønsted acid is not only a chiral
catalyst for the asymmetric [4+2] cycloaddition reaction, but
also an assistant to facilitate the gold complex catalyzed
hydroamination reaction. 31P NMR and kinetic studies
indicate that the methyl-gold complex easily reacts with
phosphoric acid to give gold phosphate at room temperature,
which shows higher catalytic activity.
Moreover, kinetic studies on the hydroamination reaction
of IIa catalyzed by different gold complexes were performed
to identify the real gold catalyst species for the second step
of the cascade catalytic reaction (Figure 2). Methyl-gold
complex showed a much lower catalytic activity than the
corresponding gold phosphate by a factor of ca. 33. This
observation, together with the fact that (L2)AuMe can be
rapidly transformed into gold phosphate 7 with 5 at room
temperature (Scheme 2), indicates that the gold phosphate 7
should be the real gold catalyst species for the hydroami-
nation reaction. Previous reports on gold(I)-catalyzed hy-
droamination of alkynes showed that the presence of
Brønsted acid facilitated the reaction to occur.13 In this case,
the presence of additional phosphoric acid 5 indeed provided
a little faster reaction. Therefore, the phosphoric acid not
only promotes the enantioselective [4+2] cycloaddition, but
Acknowledgment. We are grateful for financial support
from NSFC (20732006), MOST (973 program 2009CB825300),
Ministry of Education, and CAS.
(13) Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349.
(14) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007,
317, 496.
Supporting Information Available: Experimental details
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) (a) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986,
108, 6405. (b) Melhado, A. D.; Luparia, M.; Toste, F. D. J. Am. Chem.
Soc. 2007, 129, 12638.
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