Chiral gold complex-catalyzed hetero-diels-alder reaction of diazenes: Highly enantioselective and general for dienes

Article abstract of DOI:10.1021/ja3110472

A chiral gold(I) complex-catalyzed highly regio- and enantioselective azo hetero-Diels-Alder reaction has been developed. The chiral gold(I) complex acting as a Lewis acid exhibits high efficiency in the activation of urea-based diazene dienophiles. Moreover, this chiral gold catalyst also rendered a cascade intramolecular enyne cycloisomerization/asymmetric azo-HDA reaction.

Full text of DOI:10.1021/ja3110472

Communication
pubs.acs.org/JACS
Chiral Gold Complex-Catalyzed Hetero-Diels−Alder Reaction of
Diazenes: Highly Enantioselective and General for Dienes
Bin Liu, Kang-Nan Li, Shi-Wei Luo, Jian-Zhou Huang, Huan Pang, 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
S
* Supporting Information
The great advances have been made in the asymmetric
homogeneous gold catalysis6 since the first enantioselective
ABSTRACT: A chiral gold(I) complex-catalyzed highly
regio- and enantioselective azo hetero-Diels−Alder re-
action has been developed. The chiral gold(I) complex
acting as a Lewis acid exhibits high efficiency in the
activation of urea-based diazene dienophiles. Moreover,
this chiral gold catalyst also rendered a cascade intra-
molecular enyne cycloisomerization/asymmetric azo-HDA
reaction.
gold-catalyzed aldol reaction was described by Ito and co-
workers.7 Basically, gold(I) complexes could function either as
a σ- or π-Lewis acid.8 As π-Lewis acids, the chiral gold
complexes have been identified to render a wide range of
enantioselective transformations,6,9 whereas relatively fewer
examples have described the use of chiral gold(I) complex as σ-
Lewis acids to control the stereochemistry by coordinating to
heteroatoms (rather than C−C unsaturated bonds).7,10 In
particular, chiral gold(I) complexes have been successfully
applied to facilitate asymmetric [4 + 2] cycloaddition reaction
of allene-diene systems by coordination to carbon−carbon
unsaturated bond,11 but rarely been exploited to catalyze
asymmetric Diels−Alder reaction by lowering LUMO of
dienophiles by means of their σ-Lewis acidity. Hashmi and
co-workers have demonstrated that a nonenantioselective
tandem Diels−Alder reaction of N-phenyltriazoledione could
occur under the catalysis of gold(III) complexes.12 Herein, we
will report the first chiral gold(I) complex-catalyzed highly
enantioseletive azo-HDA reaction of diazene derivatives,
wherein a broad spectrum of easily accessible dienes could be
nicely tolerated. In addition, a cascade intramolecular enyne
cycloisomerization/asymmetric azo-HDA reaction will also be
described.
he hetero-Diels−Alder (HDA) reaction is considered one
T
of the most powerful methodologies for the construction
of multifunctionalized heterocycles.1 Among various enantio-
selective HDA reactions, those with diazene derivatives as
dienophiles were able to produce optically active piperazines,
which are important building blocks for the synthesis of natural
products and constituents of core structural elements
prevalently present in many bioactive compounds as shown
in Scheme 1.2 Moreover, the 1,4-diamine derivatives that can be
Scheme 1. The Natural Products and Bioactive Compounds
Containing Piperazine Core Structure
The initial investigation to validate our hypothesis started
with a Diels−Alder reaction between commercially available
2,4-hexadiene (1a) and urea-based diazene dienophiles 2, which
were easily prepared from commercially available aryl
isocyanates (ArNCO) and alkoxycarbonylhydrazine
(H2NNHCO2R).13 Since the chiral phosphoramidites have
been convinced to be excellent ligands in asymmetric gold
catalysis,14 a BINOL-based phosphoramidite 3a was first
examined as the ligand of gold(I) catalyst in this reaction
(Figure 1). To our delight, in the presence of 5 mol % of chiral
gold(I) complex of the phosphoramidite 3a, the HDA reaction
of diene 1a with the diazene 2a proceeded smoothly to give the
desired adduct 4a in a high yield with 44% ee (Table 1, entry
1). However, the use of diazene 2b, which was derived from 2a
by methylation, as dienophile led to no reaction (entry 2). The
comparison of this result with that observed for 2a indicated
that the proton of the nitrogen of 2a plays a crucial role in the
reaction. The counterion of gold complexes was found to exert
impact on the catalytic activities (entries 3−5) and the
accessed from piperazines have been applied to organic
synthesis of many protease inhibitors.3 However, highly
enantioselective azo-HDA reactions involving diazene dien-
ophiles are comparatively rare. Although endeavors have been
devoted to reactions of this type for many years since Jørgensen
reported a chiral copper complex-catalyzed HDA reaction with
22% ee,4 so far, only one example reported by Yamamoto and
co-workers, wherein the silver complex of BINAP enabled a
highly enantioselective HDA reaction of diazene compounds, is
most successful despite that only silyloxydienes were exploited
as substrates.5 Thus, the highly enantioseletive azo-HDA
reactions of diazene tolerating a wide scope of dienes are still
in great demand.
Received: November 9, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja3110472 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
With the optimized reaction conditions in hand, we next
explored the generality of the azo-HDA reaction (Table 2). 1,4-
a
Table 2. Substrate Scope
Figure 1. Chiral phosphoramidite ligands used in this study.
Table 1. Evaluation of Ligands and Optimization of Reaction
a
Conditions
b
c
entry
L*/X
2
T (h)
yield (%)
ee (%)
1
2
3a/NTf2
3a/NTf2
3a/SbF6
3a/OTf
3a/PF6
2a
2b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
25
12
17
17
34
4
99
N.R.
77
96
50
99
99
96
99
97
95
99
96
99
89
98
−44
--
d
3
−37
−42
−40
37
d
4
d
5
6
3b/NTf2
3c/NTf2
3d/NTf2
3e/NTf2
3f /NTf2
3g/NTf2
3h/NTf2
3c/NTf2
3d/NTf2
3e/NTf2
3h/NTf2
7
12
5
93
8
91
9
1
91
10
11
12
30
12
1
−56
−50
88
e
13
4
94
e
14
6
97
e
,f
a
15
16
6
99
Unless indicated otherwise, the reaction of 1 (0.15 mmol) and 2a
e
3
93
(0.1 mmol) was carried out at −78 °C in the presence of gold catalyst
b
c
a
of phosphoramidite 3d (5 mol %). Isolated yield. The regiomeric
The reaction of 1a (0.3 mmol) and 2 (0.1 mmol) was carried out in
dichloromethane at −78 °C in the presence of chiral gold catalyst (5
d
e
1
ratio was determined by H NMR. Determined by HPLC. Gold
f
b
c
d
catalyst of phosphoramidite 3h was used. Gold catalyst of
phosphoramidite 3e was used. 0.2 mmol of 1i (E:E/E:Z = 8:1) was
mol %). Isolated yield. Determined by HPLC. The gold catalyst
was prepared in situ from L*AuCl and AgX. In toluene. 2a was
recovered.
g
e
f
h
used. In dichloromethane.
bis(trifluoro-methylsulfonyl)amide (Tf2N−) enabled the gold
complex to exhibit the highest catalytic performance (entry 1 vs
3−5). Then, the evaluation of other BINOL- and H8−BINOL-
derived phosphoramidites 3b−h was conducted. The replace-
ment of amine moiety on the phosphoramidite ligand with
bis(1-phenylethyl)amine, as shown in 3b, led to the generation
of product with an inversed configuration (entry 6), which
indicated that the amine moiety exerted striking influence on
the control of stereochemistry. Moreover, it was identified that
the introduction of different substituents to 3,3′-positions of
the BINOL moiety has considerable impact on the stereo-
selection. Among the ligands screened, the chiral phosphor-
amidite 3c−3e and 3h were identified to deliver higher
enantioselectivity than other analogues (entries 6−12). The
examination of solvents found that the enantioselectivity could
be generally improved to some degree in toluene while the
chiral phosphoramidites 3d and 3e turned out to be most
enantioselective (entries 13−16). Although the gold complex of
3e showed higher levels of enantioselectivity than that of 3d, it
provided a slower reaction (entry 15 vs 14).
Dialkyl-substituted dienes 1b−1d could undergo [4 + 2]
cycloaddition to provide the corresponding chiral piperazines
4b−4d in high yields and with excellent enantioselectivities
ranging from 96% to 99% ee (entries 1−3). Significantly, the
azo-HDA reaction involving trisubstituted dienes, as shown in
1e−1h and 1l, also proceeded smoothly to give rise to [4 + 2]-
cycloaddition adducts in excellent enantiomeric excesses, but
interestingly, with the reversed regioselectivity (entries 4−7 and
11). More importantly, the functional groups, such as ether,
ester, and even the hydroxy group, were well tolerated (entries
1−7). Notably, the diene bearing a Lewis basic amide
participated in the HDA reaction to afford the desired product
in 99% yield with 98% ee (entry 8). A comparably lower
enantioselectivity was observed in the case involving 1,3-
cyclohexadiene (1j) as a substrate, but still with a high
enantioselectivity of 86% ee (entry 9). The [4 + 2]
cycloaddition of tetrasubstituted diene 1k proceeded cleanly
to give almost perfect yield and enantioselectivity (entry 10).
The presence of ester groups in the trisubstituted diene as
shown in 1l could also be accommodated in high yield with
B
dx.doi.org/10.1021/ja3110472 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
excellent enantioselectivity (entry 11). It is worthy to mention
that the use of the stereochemical mixtures of the dienes 1a and
1i rather than their pure form could also give high excellent
stereoselectivities, which enhanced the synthetic importance of
this reaction (Table 1 and Table 2, entry 8). The configurations
of the 4c and 4f′ were determined by X-ray analysis after
derivation (see Supporting Information).
Table 3. Cascade Intramolecular Enyne Cycloisomerization/
Asymmetric Azo HDA Reaction
a
To investigate the coordination model15 of diazene
dienophile and gold complex, the DFT calculation was
introduced.16 The located complex structures were shown in
Figure 2. The possibility of σ-coordination of the gold complex
b
c
entry
5
R1/ R2/ R3/ R4
Et/Me/H/Me
T (h) yield (%)
ee (%)
d
1
5a
5b
5c
5d
5e
5f
36
15
3
81(11)
76(15)
96
94(12)
80(6)
95
d
,e
2
3
4
5
6
7
Bn/Me/H/Me
f
Me/H/Me/Me
f
Me/H/Et/Et
3
98
91
f
Me/H/n-Pr/n-Pr
Me/H/i-Pr/i-Pr
Me/H/C2H4Ph/C2H4Ph
5
98
86
f
3
97
92
f
5g
21
95
90
a
The reaction of 5 (0.15 mmol) and 2a (0.1 mmol) was carried out in
b
PhCl with gold catalyst of 3e (5 mol %). Isolated yield of 4′, the data
c
in parentheses are yields of minor products 4. Determined by HPLC,
d
the data in parentheses are ee values of minor products 4. At 25 °C.
e
f
With gold catalyst of 3d (5 mol %). At −40 °C.
the enyne 5a was able to undergo the cascade cyclo-
isomerization/azo-Deils-Alder reaction at room temperature,
giving the 4l′ in a 81% yield and with 94% ee and over 7/1
regioselectivity (entry 1). More importantly, the extension of
the protocol to other enyne substrates was also successful. The
dibenzyl 2-allyl-2-(but-2-ynyl)malonate 5b underwent a
smooth cascade reaction, but with a sacrificed stereoselectivity
(entry 2). Significantly, the introduction of a substituent at the
vinyl moiety of 5 was also able to participate in the
enantioselective cascade reaction, to regiospecifically give the
desired products in high levels of enantioselectivity of up to
95% ee, as exemplified by the cases involving enynes 5c−5g
(entries 3−7).
Figure 2. Optimized structures at the level of B3LYP with basis set 6-
31G* for C, H, O, N, P, Cl and lanl2dz for Au atom, relative energies
in enthalpy (blue) and Gibbs free energy (red), distances in angstrom.
In conclusion, we have developed a highly regio- and
enantioselective azo-HDA reaction catalyzed by chiral gold(I)
complexes. The sterically demanding chiral phosphoramidites
turned out to be the optimal ligands for the reaction. A broad
scope of dienes was tolerated to afford structurally different
piperazine derivatives with excellent enantioselectivities. More
significantly, the π- and σ-coordination of the gold complex
enables a cascade intramolecular enyne cycloisomerization/
asymmetric azo-HDA reaction for a variety of enynes to give
piperazine derivatives in high yields and excellent levels of
stereoselectivity. Further studies will be focused on the reaction
mechanism and transition states.
to the carbonyl group of Boc was first ruled out due to its
relatively lower stability. Instead of bonding with the carbonyl
group of urea moiety as we initially proposed, it was found that
the gold preferentially formed the σ-coordination bond with the
azo moiety to lower the LUMO of the N−N double bond and
thereby facilitated the HDA reaction. The efforts to seek the π-
coordination of the gold complex to the N−N double bond of
diazene always gave the σ-coordination of gold to either oxygen
of the carbonyl or nitrogen of azo moiety. A restricted
optimization by fixing the N−N double bond of the azo moiety
and carbonyl groups in a same plane and approaching to P−Au
bond perpendicularly resulted in a located π-coordination mode
as shown in the complex-Au(I)-fixed-I (Figure 2). However, it
is less stable than the σ-coordination of gold to nitrogen of azo
moiety by about 13.5 kcal/mol.
Echavarren has established a very elegant gold(I)-catalyzed
enyne cycloisomerization, which provided an efficient entry to
access dienes of type 1l.17 Inspired by this finding, we envisaged
that it is highly possible to establish an asymmetric gold-
catalyzed cascade cycloisomerization/HDA reaction (Table 3).
In this case, the chiral gold(I) complex actually acted
sequentially as a π- and a σ-Lewis acid catalyst to promote
the whole cascade reaction. To our delight, in the presence of 5
mol % of the gold(I) complex of the chiral phosphoramidite 3e,
ASSOCIATED CONTENT
* Supporting Information
Complete experimental procedures and characterization data
for the prepared compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
gonglz@ustc.edu.cn
■
Notes
The authors declare no competing financial interest.
C
dx.doi.org/10.1021/ja3110472 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Faustino, H.; Iglesias-Siguenza, J.; Díez, E.; Alonso, I.; Fernan
́
dez, R.;
̈
ACKNOWLEDGMENTS
■
Lassaletta, J. M.; Lop
134, 14322.
(12) Hashmi, A. S. K.; Kurpejovic,
W. Adv. Synth. Catal. 2007, 349, 1743.
(13) Lenarsic, R.; Kocevar, M.; Polanc, S. J. Org. Chem. 1999, 64,
2558.
(14) (a) Suar
J. M. Angew. Chem., Int. Ed. 2012, 51, 1. (b) Teller, H.; Flugge, S.;
́
ez, F.; Mascarenas, J. L. J. Am. Chem. Soc. 2012,
̃
We are grateful for financial support from NSFC (21232007,
21072181), MOST (973 project 2010CB833300), Ministry of
Education, and CAS.
́
E.; Wolfle, M.; Frey, W.; Bats, J.
̈
̌
̌
̌
REFERENCES
■
́
́ ́
ez-Pantiga, S.; Hernandez-Díaz, C.; Rubio, E.; Gonzalez,
(1) For a general review of HDA reactions, see: (a) The Diels-Alder
Reaction: Selected Practical Methods; Fringuelli, F., Taticchi, A., Eds.;
John Wiley & Sons: New York, 2002. (b) Cycloaddition Reactions in
Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH:
Weinheim, Germany, 2002; pp 151−209. (c) Comprehensive
Asymmetric Catalysis III; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; pp 1237−1254. (d) Gouverneur, V.;
Reiter, M. Chem.Eur. J. 2005, 11, 5806. (e) Jørgensen, K. A. Angew.
Chem., Int. Ed. 2000, 39, 3558. (f) Tietze, L. F.; Kettschau, G. Top.
Curr. Chem. 1997, 189, 1. (g) Pellissier, H. Tetrahedron 2009, 65,
2839. (h) Lin, L.-L.; Liu, X.-H.; Feng, X.-M. Synlett 2007, 14, 2147.
(i) Yamamoto, H.; Kawasaki, M. Bull. Chem. Soc. Jpn. 2007, 80, 595.
(2) (a) Alves, M. J.; Costa, F. T.; Duarte, V. C.; Fortes, A. G.;
Martins, J. A.; Micaelo, N. M. J. Org. Chem. 2011, 76, 9584.
(b) Moreno-Clavijo, E.; Carmona, A. T.; Moreno-Vargas, A. J.;
̈
Goddard, R.; Furstner, A. Angew. Chem., Int. Ed. 2010, 49, 1949.
̈
(c) Teller, H.; Furstner, A. Chem.Eur. J. 2011, 17, 7764.
̈
(d) Gonzal
́
ez, A. Z.; Benitez, D.; Tkatchouk, E.; Goddard, W. A.,
III; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 5500. (e) Gonzal
́
ez, A.
Z.; Toste, F. D. Org. Lett. 2010, 12, 200.
(15) Theoretical Inorganic Chemistry II; Albini, A., Kisch, H., Eds.;
Springer: Berlin, 1976; pp 105−145.
(16) The calculations were carried out with the Gaussian 03: Frisch,
M. J. et al.; Gaussian03, revisionD.03; Gaussian, Inc.: Wallingford, CT.,
2004 (for complete ref 16, see the Supporting Information).
(17) Cabello, N.; Jimen
Echavarren, A. M. Eur. J. Org. Chem. 2007, 4217.
́
ez-Nuuez, E.; Bunuel, E.; Cardenas, D. J.;
́
́
̃
̃
́
Alvarez, E.; Robina, I. Synlett 2010, 9, 1367. (c) Moreno-Clavijo, E.;
́
Carmona, A. T.; Moreno-Vargas, A. J.; Rodrıguez-Carvajal, M. A.;
Robina, I. Bioorg. Med. Chem. 2010, 18, 4648. (d) Li, W.-H.; Gan, J.-
G.; Ma, D.-W. Angew. Chem., Int. Ed. 2009, 48, 8891. (e) Phillip
Kennedy, J.; Brogan, J. T.; Lindsley, C. W. Tetrahedron Lett. 2008, 49,
4116.
(3) (a) Chapman, S. K.; Glant, S. K. J. Pharm. Sci. 1980, 69, 733.
(b) Ducep, J. B.; Heintzelmann, B.; Jund, K.; Lesur, B.; Schleimer, M.;
Zimmermann, P. R. Tetrahedron: Asymmetry 1997, 8, 327.
(c) Oscarsson, K.; Oscarson, S.; Vrang, L.; Hamelink, E.; Hallberg,
A.; Samuelsson, B. Bioorg. Med. Chem. 2003, 11, 1235. (d) Zuccarello,
G.; Bouzide, A.; Kvarnstrom, I.; Niklasson, G.; Svensson, S. C. T.;
̈
́
Brisander, M.; Danielsson, H.; Nillroth, U.; Karlen, A.; Hallberg, A.;
Classon, B.; Samuelsson, B. J. Org. Chem. 1998, 63, 4898.
(4) Aburel, P. S.; Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Org .
Biomol. Chem. 2005, 3, 2344.
(5) Kawasaki, M.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 16482.
(6) For selected reviews of asymmetric homogeneous gold catalysis,
see: (a) Windenhoefer, R. A. Chem.Eur. J. 2008, 14, 5382.
(b) Sengupta, S.; Shi, X.-D. ChemCatChem 2010, 2, 609. (c) Pradal,
A.; Toullec, P. Y.; Michelet, V. Synthesis 2011, 10, 1501.
(7) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108,
6405.
(8) For a example that gold(I) complex unified both σ- or π-Lewis
acid properties, see: Boiaryna, L.; El Mkaddem, M. K.; Taillier, C.;
Dalla, V.; Othman, M. Chem.Eur. J. 2012, 18, 14192.
(9) For selected reviews of examples that gold(I) complexes
functioned as π-Lewis acids, see: (a) Gorin, D. J.; Toste, F. D. Nature
2007, 446, 395. (b) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
(c) Arcadi, A. Chem. Rev. 2008, 108, 3266. (d) Gorin, D. J.; Sherry, B.
D.; Toste, F. D. Chem. Rev. 2008, 108, 3351. (e) Li, Z.; Brouwer, C.;
He, C. Chem. Rev. 2008, 108, 3239.
́ ́
(10) (a) Martín-Rodríguez, M.; Najera, C.; Sansano, J. M.; de Cozar,
A.; Cossío, F. P. Chem.Eur. J. 2011, 17, 14224. (b) Jagdale, A. R.;
Youn, S. W. Eur. J. Org. Chem. 2011, 2011, 3904. (c) Jagdale, A. R.;
Park, J. H.; Youn, S. W. J. Org. Chem. 2011, 76, 7204. (d) Dombray,
T.; Blanc, A.; Weibel, J. M.; Pale, P. Org. Lett. 2010, 12, 5362. (e) Lin,
C.-C.; Teng, T.-M.; Odedra, A.; Liu, R.-S. J. Am. Chem. Soc. 2007, 129,
3798. (f) Lin, C.-C.; Teng, T.-M.; Tsai, C.-C.; Liao, H.-Y.; Liu, R.-S. J.
Am. Chem. Soc. 2008, 130, 16417. (g) Melhado, A. D.; Amarante, G.
W.; Wang, Z. J.; Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2011, 133,
3517.
(11) (a) Gonzal
(b) Alonso, I.; Trillo, B.; Lop
Castedo, L.; Lledos, A.; Mascarenas, J. L. J. Am. Chem. Soc. 2009, 131,
13020. (c) Teller, H.; Flugge, S.; Goddard, R.; Furstner, A. Angew.
́
ez, A. Z.; Toste, F. D. Org. Lett. 2010, 12, 200.
́
ez, F.; Montserrat, S.; Ujaque, G.;
́
̃
̈
̈
Chem., Int. Ed. 2010, 49, 1949. (d) Francos, J.; Grande-Carmona, F.;
D
dx.doi.org/10.1021/ja3110472 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX