Synthesis of fused bicyclic aminals through sequential gold/Lewis acid catalysis

Article abstract of DOI:10.1021/ol400803f

A novel sequential catalysis by combining gold catalysis with early transition metal catalysis was developed. Biologically important bicyclo[4.n.0] aminals were obtained under very mild conditions.

Full text of DOI:10.1021/ol400803f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of Fused Bicyclic Aminals
through Sequential Gold/Lewis Acid
Catalysis
Xianghua Wang,† Zhili Yao,† Shuli Dong,† Fang Wei,† Hong Wang,‡ and Zhenghu Xu*,†
Key Lab for Colloid and Interface Chemistry of Education Ministry School of Chemistry
and Chemical Engineering, Shandong University, Jinan 250100, China, and Department
of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States
Xuzh@sdu.edu.cn
Received March 25, 2013
ABSTRACT
A novel sequential catalysis by combining gold catalysis with early transition metal catalysis was developed. Biologically important bicyclo[4.n.0]
aminals were obtained under very mild conditions.
Bicyclic aminals and a similar structure presented a key
structural unit in many bioactive natural products as well
as pharmaceuticals (Figure 1). For example, the Nomo-
fungin/Communesin family, a group of eight architectu-
rally intriguing indole alkaloids bearing two fused bicyclic
aminal moieties, have attracted much attention in recent
years.1 They show good cytotoxic acitivity. Artemisinin, a
polycyclic acetal, is the most effective antimalaria agent.2
The commercial pharmaceutical Physostigmine, a para-
sympathomimetic alkaloid, is used to treat myasthenia
gravis, glaucoma, and Alzheimer’s disease.3 Perinadine
A, the tetracyclic alkaloid bearing fused bicyclic N,O-
Figure 1. Natural products and pharmaceuticals containg fused
bicyclic aminals and acetals.
aminals, is a biologically active secondary metabolite and
a rigid spiroketal structure wasrecentlyusedasanexcellent
shows cytotoxicity and antibacterial activity.4 In addition,
chiral ligand for asymmetric catalysis.5 Thus efficient
synthetic methodology toward this structural target is in
† Shandong University.
‡ Miami University.
great demand. The current access methods mainly include
stepwise acetalization from preformed multifunctionlized
substrates. Cascade reactions provide an efficient way to
construct complex molecular structures from readily avail-
able fragments with great operation and step ecconomy.6a
Recently, an efficient gold-catalyzed tandem reaction
(1) (a) Siengalewicz, P.; Gaich, T.; Mulzer, J. Angew. Chem., Int. Ed.
2008, 47, 8170. (b) Numata, A.; Takahashi, Ch.; Ito, Y.; Takada, T.;
Kawai, K.; Usami, Y.; Matsumura, E.; Imachi, M. Tetrahedron Lett.
1993, 34, 2355. (c) Belmar, J.; Funk, R. L. J. Am. Chem. Soc. 2012, 134,
16941. (d) Zuo, Z.; Ma, D. Angew. Chem., Int. Ed. 2011, 50, 12008. (e)
Yang, J.; Wu, H. X.; Shen, L. Q.; Qin, Y. J. Am. Chem. Soc. 2007, 129,
13794.
(2) (a) Zhou, W. S.; Xu, X. X. Acc. Chem. Res. 1994, 27, 211. (b)
Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem.
Res. 2008, 41, 40. (c) Zhu, C.; Cook, S. P. J. Am. Chem. Soc. 2012, 134,
13577.
(3) Militante, J.; Ma, B. W.; Akk, G.; Steinbach, H. Mol. Pharmacol.
2008, 74, 764.
(4) Sasaki, M.; Tsuda, M.; Sekiguchi, M.; Mikami, Y.; Kobayashi, J.
(5) (a) Wang, X.; Han, Z.; Wang, Z.; Ding, K. Angew. Chem., Int. Ed.
2012, 51, 936. (b) Wang, X.; Meng, F.; Wang, Y.; Han, Z.; Chen, Y.; Liu,
L.; Wang, Z.; Ding, K. Angew. Chem., Int. Ed. 2012, 51, 9276.
(6) (a) Hashmi, A. S. K.; Hubbert, C. Angew. Chem., Int. Ed. 2010,
€
€
49, 1010. (b) Hashimi, A. S. K.; Buhrle, M.; Wolfle, M.; Rudolph, M.;
Org. Lett. 2005, 7, 4261.
Wieteck, M.; Rominger, F.; Frey, W. Chem.;Eur. J. 2010, 16, 9846.
r
10.1021/ol400803f
XXXX American Chemical Society

toward tricyclic cage-like N,O-acetals has been reportedby
the Hashimi group.6b Herein we will report a bimetallic
Lewis acid (Au (I) and Ga(III)) sequential catalyzed
cascade reaction to access fused bicyclic aminals.
Scheme 1. Concept of the Bimetallic Lewis Acid Catalyzed
Intramolecular Hydroamination/Inverse-Electron-Demand
Hetero-DielsꢀAlder Reaction Cascade
Gold-catalyzed reactions have been intensively investi-
gated and applied in multistep syntheses in the past
decade.7,8 Recently Gong and others developed a series
of gold(I)/Bronsted acid relay catalysis and turned out to
be a robust strategy to assemble readily available starting
materials into structually complex molecules.9 But the
combination of gold catalysis with another metal Lewis
acid is still very rare.9b,10 We can envision that if we can
combine the π-acid gold with another σ metal Lewis acid
such as early transition metal lanthanide, a dual activation
mode of both substrates will be formed and many new
reactions and new chemistry can be developed.
Enamine, which is normally generated from the dehy-
dration reaction of an amine witha carbonyl group, played
a very important role in the current aminocatalysis.11
Gold(I)-catalyzed hydroamination of an alkyne will also
generate enamine utilizing an alternative approach. Very
recently, Che and Stradiotto reported the intermolecular
hydroamination of alkyne with an aromatic amine or
aliphatic amine by using a gold catalyst with a bulky
phosphine ligand.12 The produced enamine would isomer-
ize into imine very easily, which was reduced to amine in
these two reports. Hammond and Xu reported the tandem
intramolecular hydroamination/isomerization into imine/
nucleophilic addition reactions to prepare different N-het-
erocycles (Scheme 1).13 We have developed an Inverse-
Electron-Demand Hetero-DielsꢀAlder (IED-HDA) reac-
tion of cyclohexanone with unsaturated β-ketone ester 1 in
the presence of an Y(OTf)3-primary amine bifunctional
catalyst.14 Ketone ester 1 was greatly activated by the early
transition metal Y(OTf)3 through chelating coordination
and thus reacted with the in situ generated enamine from
cyclohexanone very rapidly. Therefore we are going to
extend this methodology to the bimetallic cooperative
catalysis: the alkyne amines 2 underwent a cycloisomeriza-
tion reaction to afford the enamine by a gold(I) catalyst,
and then the enamine was trapped by another Lewis
activated electrophile 1 through the IED-HDA reaction
to produce the important bicyclic aminals.15
(7) For selected reviews, see: (a) Zhang, L.; Sun, J.; Kozmin, S. A.
€
Adv. Synth. Catal. 2006, 348, 2271. (b) Furstner, A.; Davies, P. W.
Angew. Chem., Int. Ed. 2007, 46, 3410. (c) Li, Z.; Brouwer, C.; He, C.
ꢀ
ꢀ
Chem. Rev. 2008, 108, 3239. (d) Jimenez- Nunez, E.; Echavarren, A. M.
Chem. Rev. 2008, 108, 3326. (e) Gorin, D. J.; Sherry, B. D.; Toste, F. D.
Chem. Rev. 2008, 108, 3351. (f) Hashmi, A. S. K.; Rudolph, M. Chem.
Soc. Rev. 2008, 37, 1766. (g) Hashmi, A. S. K. Angew. Chem., Int. Ed.
2010, 49, 5232. (h) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria,
M.; Simonneau, A. Chem. Rev. 2011, 111, 1954. (i) Patil, N. T.;
Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (j) Krause, N.; Winter, C.
Chem. Rev. 2011, 111, 1994. (k) Rudolph, M.; Hashmi, A. S. K. Chem.
Soc. Rev. 2012, 41, 2448.
(8) For recent examples, see: (a) Tkatchouk, E.; Mankad, N. P.;
Benitez, D.; Goddard, W. A.; Toste, F. D. J. Am. Chem. Soc. 2011, 133,
14293. (b) Pagar, V. V.; Jadhav, A. M.; Liu, R.-S. J. Am. Chem. Soc.
2011, 133, 20728. (c) Jadhav, A. M.; Bhunia, S.; Liao, H. Y.; Liu, R.-S.
J. Am. Chem. Soc. 2011, 133, 1769. (d) Chen, Y.; Chen, M.; Liu, Y.
Angew. Chem., Int. Ed. 2012, 51, 6493. (e) Chen, Y.; Li, G.; Liu, Y. Adv.
Synth. Catal. 2011, 353, 392. (f) Conyers, R. C.; Gung, B. W. Chem.;
Eur. J. 2013, 19, 654. (g) Gung, B. W.; Craft, D. T.; Bailey, L. N.;
Kirschbaum, K. Chem.;Eur. J. 2010, 16, 639. (h) Liu, F.; Qian, D.; Li,
L.; Zhao, X.; Zhang, J. Angew. Chem., Int. Ed. 2010, 51, 6669. (i) Yang,
T.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2007, 129, 12070. (j) Ye,
L.; He, W.; Zhang, L. Angew. Chem., Int. Ed. 2011, 50, 3236. (k) Ye, L.;
Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 3258. (l) Ye,
L.; He, W.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 8550. (m) Cui, L.;
Peng, Y.; Zhang, L. J. Am. Chem. Soc. 2009, 131, 8394. (n) Wang, D.;
Cai, R.; Sharma, S.; Jirak, J.; Thummanapelli, S. K.; Akhmedov, N. G.;
Zhang, H.; Liu, X.; Petersen, J. L.; Shi, X. J. Am. Chem. Soc. 2012, 134,
9012. (o) Wang, Q.; Aparaj, S.; Akhmedov, N. G.; Petersen, J. L.; Shi, X.
Org. Lett. 2012, 14, 1334. (p) Wang, D.; Gautam, L. N. S.; Bollinger, C.;
Harris, A.; Li, M.; Shi, X. Org. Lett. 2011, 13, 2618. (q) Xu, M.; Ren,
T.-T.; Li, C.-Y. Org. Lett. 2012, 14, 4902. (r) Xu, C.-F.; Xu, M.; Yang,
L.-Q.; Li, C.-Y. J. Org. Chem. 2012, 77, 3010. (s) Shu, C.; Liu, M.; Sun,
Y.; Ye, L. Org. Lett. 2012, 14, 4958. (t) Xu, C.-F.; Xu, M.; Jia, Y.-X.; Li,
C.-Y. Org. Lett. 2011, 13, 1556. (u) Shu, C.; Liu, M.; Wang, S.; Li, L.; Ye,
L. J. Org. Chem. 2013, 78, 3292. (v) Sun, J.; Conley, M. P.; Zhang, L.;
Kozmin, S. A. J. Am. Chem. Soc. 2006, 128, 9705. (w) Fan, T.; Chen, X.;
Sun, J.; Lin, Z. Organometallics 2012, 31, 4221.
Following this strategy, alkynes 2 and unsaturated
β-ketone ester 1a were subjected to this cascade reaction
in the presence of AuCl3 and Y(OTf)3 in THF at rt
(Scheme 2). It was found that the substituent on the amine
part played a very important role in this transformation.
When it is the primary amine (2a, R = H) and secondary
amine (2b, R = Bn), a messy reaction mixture was
(12) (a) Liu, X.; Che, C.-M. Org. Lett. 2009, 11, 4204. (b) Hesp, K. D.;
Stradiotto, M. J. Am. Chem. Soc. 2010, 132, 18026.
(13) (a) Han, J.; Xu, B.; Hammond, G. B. Org. Lett. 2011, 13, 3450.
(b) Han, J.; Xu, B.; Hammond, G. B. J. Am. Chem. Soc. 2010, 132, 916.
(14) (a) Xu, Z.; Liu, L.; Wheeler, K.; Wang, H. Angew. Chem., Int.
Ed. 2011, 50, 3484. (b) Xu, Z.; Wang, H. Synlett 2011, 2907.
(15) For Povarov reaction type multicomponent reactions from
(9) (a) Han, Z.; Chen, D.; Wang, Y.; Guo, R.; Wang, P.; Wang, C.;
Gong, L.-Z. J. Am. Chem. Soc. 2012, 134, 6532. (b) Wu, H.; He, Y.;
Gong, L.-Z. Adv. Synth. Catal. 2012, 354, 975. (c) Tu, X.; Gong, L.-Z.
Angew. Chem., Int. Ed. 2012, 51, 11346. (d) Ren, L.; Lei, T.; Ye, J.; Gong,
L.-Z. Angew. Chem., Int. Ed. 2012, 51, 771. (e) Wang, C.; Han, Z.; Luo,
H.; Gong, L.-Z. Org. Lett. 2010, 12, 2266. (f) Han, Z.; Xiao, H.; Chen,
X.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 9182.
ꢀ
alkynol, see: (a) Barluenga, J.; Mendoza, A.; Rodriguez, F.; Fananas,
(10) For four more examples of gold participating in cooperative dual
metal catalysis, see: (a) Wang, Y.; Liu, L.; Zhang, L. Chem. Sci. 2013, 4,
739. (b) Egi, M.; Yamaguchi, Y.; Fujiwara, N.; Akai, S. Org. Lett. 2008, 10,
1867. (c) Ye, L.; Zhang, L. Org. Lett. 2009, 11, 3646. (d) Demir, A. S.;
Emrullahoglu, M.; Buran, K. Chem. Commun. 2010, 46, 8032.
(11) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471.
F. J. Angew. Chem., Int. Ed. 2008, 47, 7044. (b) Barluenga, J.; Mendoza,
ꢀ
A.; Rodriguez, F.; Fananas, F. J. Angew. Chem., Int. Ed. 2009, 48, 1644.
ꢀ
(c) Barluenga, J.; Mendoza, A.; Rodriguez, F.; Fananas, F. J. Chem.;
Eur. J. 2008, 14, 10892. (d) Barluenga, J.; Calleja, J.; Mendoza, A.;
ꢀ
Rodriguez, F.; Fananas, F. J. Chem.;Eur. J. 2010, 16, 7110. (e)
ꢀ
Fananas, F. J.; Mendoza, A.; Arto, T.; Temelli, B.; Rodriguez, F.
Angew. Chem., Int. Ed. 2012, 51, 4930.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Reaction Conditionsa
Scheme 2. Initial Formation of the Unexpected Fused Bicyclic
Aminals
produced under these conditions. Fortunately, when we
use the Ts group (R = 4-toluenesulfonyl, 2c), product 3a
was isolated in 30% yield. To our great surprise, it is not
the expected spiro-aminal 3a0, but the fused bicyclo[4.3.0]
aminal 3a. The structure was confirmed by single crystal
X-ray analysis. More important, only the endo-diastereomer
was obtained in this reaction.
Inspired by the observed results, we continued to opti-
mize the reaction conditions to develop an efficient bime-
tallic Lewis acid catalyzed system toward fused bicyclic
aminals (Table 1). Solvent screening showed that toluene
was the optimal solvent, and the reaction yield increased to
76% yield in 1.5 h (for details, see the Supporting
Information). During this process, we found that there is
certain amount of the spiro-aminals by careful analysis of
1H NMR spectra of the mixture (3a/3a0 = 2.3/1, entry 2).
Then a variety of different π-acid metal catalysts with
Y(OTf)3 were examined. Different gold catalysts, Pd(OAc)2,
andCuOTfalldisplayedveryhighactivitytowardthebicyclic
aminals (entries 3ꢀ11), and AuCl(CH3SCH3) afforded the
products in the highest yield (96%), although the chemos-
electivity is still only 2.3/1 (3a/3a0, entry 7). In order to
improve the chemoselectivity, we investigated different early
transition metals such as In(OTf)3, Sc(OTf)3, Ga(OTf)3,
La(OTf)3, and Bi(OTf)3 together with AuCl(CH3SCH3) as
the π-acid (entries 12ꢀ16). Among all of them, Ga(OTf)3 was
the best choice and resulted in the formation of the fused
bicyclic aminal 3a in 81% yield with good chemoselectivity
(f/s = 6.6/1, entry 14), although a trace amount of another
exo-diastereomer of 3a was detected from 1H NMR.
a Reaction conditions: 2c (0.2 mmol), 1a (0.24 mmol), catalyst A
(5 mol %), catalyst B (10 mol %), solvent (2 mL) at 40 °C for 1.5 h.
b Determined by crude 1H NMR; “f” represents a fused product, and “s”
represents a spiro product. c Isolated yield of combined products.
d Diastereoselectivity ratio: endo/exo = 13/1.
generate the corresponding bicyclo[4.4.0] aminals (4aꢀ4c)
in moderate yield in the presence of PPh3AuNTf2
(5 mol %) and Ga(OTf)3 (10 mol %) (eq 1). Substrate 2e
bearing onelesscarbonalsoproceededsmoothlygivingthe
bicyclo[4.3.0] aminal 5 in 65% yield with very moderate
diastereoselectivity (endo/exo = 1/1, eq 2). Besides, the
alkynyl alcohol 2f was also effective, affording the bicyclo-
[4.3.0] ketal 6 as the major product in 55% yield (eq 3).
With the optimized conditions in hand, the substrate
scope was examined (Scheme 3). Different halogen groups
on the para or ortho position of the phenyl ring and
different ester groups favored the reaction, providing
corresponding products in good to excellent yields
(3aꢀ3f, 3l). Substrates bearing an electron-donating group
such as methyl and methoxyl were also suitable substrates,
giving the desired aminals in 65% yield (3g, 3h). Electron-
withdrawing groups favored this IED-HDA reaction
greatly and affored the product 3n in the highest 90%
yield. In addition, more sensitive substituents such as
styryl, 2-furyl, and 2-thienyl were well tolerated in this
mild transformation and the corresponding products were
obtained in 62ꢀ65% yield (3i, 3j, 3k).
In order to further probe the scope of this reaction,
different alkynyl amines were investigated. Substrate 2d
bearing one more carbon chain reacted smoothly with 1 to
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Scope of the Au(I)ꢀGa(III) Catalyzed Cascade
Scheme 4. Proposed Mechanism
Reactiona
cycloaddition with the Lewis acid activated electrophile
generating the final product.
a Reaction conditions: 2c (0.2 mmol), 1 (0.24 mmol), Au(CH3SCH3)Cl
(5 mol %), Ga(OTf)3 (10 mol %), toluene (2 mL) at 40 °C for 1.5 h.
Isolated yield of combined products and the number in parentheses
b
represent the isolated yield of fused bicyclic aminals. The crude 1H
In summary, we have described a new synthetic strategy
based upon a one-pot sequential gold-catalysis/Lewis acid
catalysis. The biologically important bicyclo[4.n.0] aminals
were synthesized in high efficiency under very mild condi-
tions. This type of combination of a π-acid with another σ
metal Lewis acid will find more applications in organic
synthesis.
NMR was complicated, making determination of the selectivity
difficult.
To gain insights into the reaction mechanism, we con-
ducted deuteration experiments. The reaction was per-
formed under standard conditions with an additional 5
equiv of D2O, and the newly formed methyl group was
30% deuterated (eq 4). We also prepared 2c-d, which was
deuterated 100% at the alkyne terminus, and the reaction
led to 2c-d having a 33% deuterium content at the methyl
position (eq 5). If 5 equiv of D2O were added into the
reaction of 2c-d, the methyl group was 60% deuterated
(eq 6). More important, during the reactions, the proton at
the methylene group adjacent to the triple bond was
deuterated in the presence of D2O and lost a D atom in
the absence of D2O (eqs 5 and 6) . These data indicated that
there is an equilibrium between enamide M1 and M2, and
M2 is favored (Scheme 4).11 Thus we proposed the possible
mechanism: the gold catalyzed 5-exo-dig cyclization af-
fording the enaminde M1, followed by isomerization into
the more stable enamide M2, followed by the [4 þ 2]
Acknowledgment. We are grateful for financial support
from the Natural Science Foundation of China (Grant No.
21102085), Science Foundation of Ministry of Education
of China (No. 20110131120049), and Natural Science
Foundation of Shandong Province (BS2012-YY006). We
thank Dr. Prof. Daofeng Sun and Dr. Di Sun for the X-ray
structure analysis.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX