Direct access to enantioenriched spiroacetals through asymmetric relay catalytic three-component reaction

Article abstract of DOI:10.1021/ol303188u

The gold(I)/chiral Br?nsted acid relay catalysis enabled a highly stereoselective three-component reaction of salicylaldehydes, anilines, and alkynols to give aromatic spiroacetals in high yields and stereoselectivities.

Full text of DOI:10.1021/ol303188u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Direct Access to Enantioenriched
Spiroacetals through Asymmetric Relay
Catalytic Three-Component Reaction
Hua Wu, Yu-Ping He, 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 November 19, 2012
ABSTRACT
The gold(I)/chiral Brønsted acid relay catalysis enabled a highly stereoselective three-component reaction of salicylaldehydes, anilines, and
alkynols to give aromatic spiroacetals in high yields and stereoselectivities.
The spiroacetal moiety widely presented in a myriad of
natural products essentially contributes to the bioactivity
and represents a privileged scaffold in drug discovery.1
Moreover, molecules containing the spiroacetal have been
widely recognized as useful building blocks for the synth-
esis of a wide range of biologically active compounds,2
such as berkelic acid(I), which shows a confrontation
ovarian cancer effect, paecilospirone (II), which acts as
an inhibitor of microtubule, and γ-rubromycin (III), which
exhibits antibacterial properties (Figure 1). Consequently,
efficient access to such a structural target has been in great
demand. However, the methods investigated previously
reported mostly on the diastereoselective spiroacetaliza-
tions from optically pure starting matierals,3 and until very
Figure 1. Nature products containing spiroacetal moiety.
recently, the asymmetric catalytic variants from achiral
materials to give optically active spiroacetal have not
appeared.4,5 Ding and co-workers reported a nice synthesis
of spiroacetals with excellent levels of stereoselectivity
(1) For reviews see: (a) Perron, F.; Albizati, K. F. Chem. Rev. 1989,
89, 1617. (b) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105,
4406.
(2) For selected early reports on total synthesis of nature products
through asymmetric reductive acetalization of R,β-unsa-
containing spiroacetal motifs, see: (a) Zinzalla, G.; Milroy, L.; Ley, S. V.
turated ketones catalyzed by chiral iridium(I) complexes
Org. Biomol. Chem. 2006, 4, 1977. (b) Milroy, L.; Zinzalla, G.; Prencipe,
(eq 1, Scheme 1).4a List identified a truly enantioselective
G.; Michel, P.; Ley, S. V.; Gunaratnam, M.; Beltran, M.; Neidle, S.
Angew. Chem., Int. Ed. 2007, 119, 2545. (c) Yuen, T.; Yang, S.; Brimble,
M. A. Angew. Chem., Int. Ed. 2011, 50, 8350.
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T. R. R. Org. Lett. 2008, 10, 1477. (b) Wilson, Z. E.; Hubert, J. G.;
Brimble, M. A. Eur. J. Org. Chem. 2011, 3938. (c) Smith, M. J.; Furkert,
D. P.; Sperry, J.; Brimble, M. A. Synlett 2011, 1395. (d) Butkevich, A. N.;
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2012, 51, 936–940. (b) Coric, I.; List, B. Nature 2012, 483, 315. (c) Sun,
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r
10.1021/ol303188u
XXXX American Chemical Society

acetalization of hydroxyalkyl-substituted enol ethers by
using a newly designed chiral binol-based C2-symmetric
imidodiphosphoric acid as the chiral catalyst, generating
chiral spiroacetals in excellent stereoselectivity (eq 2,
Scheme 1).4b Subsequently, Nagorny established a similar
binol-based phosphoric acid-catalyzed stereoselective acet-
more synthetically efficient access to the structurally com-
plex targets, has been investigated even less and is thereby
highly valuable to be disclosed.5 We will herein report a
gold(I)/Brønsted acid relay catalytic three-component
cascade reaction, providing an important alternative of
known methods to directly access highly enantioenriched
spiroacetals.
Scheme 1. Typical Examples of Asymmetric Catalytic Access to
Chiral Spiroacetals
Scheme 2. Asymmetric Gold(I)/Brønsted Acid Relay Catalytic
Synthesis of Spiroacetals
In the last decades, the metal/organo combined catalysis
has turned out to be a robust strategy for the creation of
new enantioselective transformations.6ꢀ8 In particular, the
hybrid metal/organo relay catalysis was able to assemble
readily available starting materials into structurally com-
plex molecules, essentially avoiding additional laborious
workup and purification process of the intermediates
involved.8 We and others found that the combination of
gold complexes and chiral phosphoric acids enabled a
range of asymmetric cascade reactions.8 Recently, Bar-
luenga developed a palladium(II)-catalyzed synthesis of
racemic spiroacetals through a three-component cascade
reaction.9 Inspired by this finding and our knowledge in
gold/phosphoric acid binary catalysis,8d,h,kꢀm we envi-
saged that the alkynols of type 1 are principally able to
undergo a cyclization reaction to afford aromatic enol ethers
A under the catalysis of a gold complex.8k The intermedi-
ates A might participate in a formal [4 þ 2] cyclization reac-
tion, consisting of an asymmetric Mannich-type reaction
alization of hydroxyalkyl-substituted enol ethers (eq 3,
Scheme 1).4c Despite these successful examples, the union
of readily available and easily accessible fragments instead
of the preformed acetalization substrates into chiral spir-
oacetals under mild conditions, which actually provides a
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see: (a) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745. (b) de
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Gajula, B. Org. Biomol. Chem. 2012, 10, 211.
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Yoshida, K.; Miyabe, H.; Takemoto, Y. Angew. Chem., Int. Ed. 2003,
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Adv. Synth. Catal. 2007, 349, 1891. (b) Chercheja, S.; Eilbracht, P. Adv.
Synth. Catal. 2007, 349, 1897. (c) Sorimachi, K.; Terada, M. J. Am.
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(k) Han, Z.-Y.; Guo, R.; Wang, P.-S.; Chen, D.-F.; Xiao, H.; Gong, L.-Z.
Tetrahedron Lett. 2011, 52, 5963. (l) Han, Z.-Y.; Chen, D.-F.; Wang, Y.-Y.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

with salicylaldehydimines B in situ generated from the
condensation between salicylaldehydes 2 and anilines 310
under the catalysis of chiral Brønsted acid11 and a subse-
quent acetalization to result in the generation of corre-
sponding aromatic spiroacetals (Scheme 2). As such, a
series of enantioenriched aromatic spiroacetals would be
directly afforded from easily accessible substrates.
Table 1. Evaluation of Brønsted Acid Catalysts and Optimiza-
tion of Reaction Conditionsa
The initial investigation of the proposed asymmetric
relay catalytic three-component reaction was performed
with (2-ethynylphenyl)methanol (1a), 2-hydroxybenzalde-
hyde (2a), and aniline (3) in the presence of a combined
catalyst system8d consisting of chiral gold phosphate and
Brønsted acids prepared from PPh3AuMe (5 mol %) and
chiral phosphoric acid 5a (10 mol %) and of 4 A molecular
sieves in fluorobenzene12 at 10 °C (Table 1). The transfor-
mation proceeded smoothly and afforded N-phenyl-30H-
spiro[chroman-2,10-isobenzofuran]-4-amine (4a) in good
yield (70%), but the enantioselecitivity was poor (entry 1).
Thus, various structurally diverse chiral phosphoric acids
5aꢀg derived from 3,30-disubstituted BINOLs were eval-
uated to identify the best orgnaocatalyst (entries 2ꢀ7).
Among them, the phosphoric acid 5g bearing a sterically
bulky substituents at 3,30-positions turned out to be the
preeminent catalyst and was able to provide the spiroacetal
4a with high yield (83%) and moderate diastereoselectivity
(3:1), while the major diastereomer of 4a was obtained in
72% ee(entry 7). Interestingly, thechiralgold phosphatein
situ generated from 5g and PPh3AuMe8d,e was able to
catalyze the reaction in 79% yield, but with a lower
enantioselectivity (entry 8 vs 7). The results indicated that
both gold phosphate and chiral phosphoric acid can
catalyze the cascade reaction, but the chiral phosphoric
acid plays a dominant role in the control of stereoselectiv-
ity in the Mannich-type reaction step (Scheme 2). A survey
of solvents identified that the halogenated benzenes were
beneficial to the stereocontrol (entries 9ꢀ11), and enan-
tioselectivity could be enhanced to 80% ee by conducting
the reaction in 1,2,4-trichlorobenzene (entry 11). Then, a
variety of aniline derivatives (3bꢀe) were examined, and it
was found that either electronically withdrawing or donat-
ing substituents were well tolerated (entries 12ꢀ15). In
particular, the 3,5-dimethoxyaniline (3e) participated in
the three-component reaction with the highest level of
enantioselectivity (entry 15).
entry
B*-H
ArNH2
4
yieldb (%)
drc
3/1
eed (%)
1
2
5a
5b
5c
5d
5e
5f
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
70
99
65
73
93
87
83
79
80
78
84
75
83
69
88
1
10
3/1
3
3/1
21
4
3/1
49
5
3/1
19
6
3/1
6
7
5g
5g
5g
5g
5g
5g
5g
5g
5g
3/1
72
8
3/1
65e
74f
76g
80h
76h,i
74h,i
69h,i
85h,i
9
4/1
10
11
12
13
14
15
4.6/1
4.5/1
4.3/1
4.7/1
4.5/1
6/1
a Unless indicated otherwise, the reaction of 1 (0.12 mmol), 2 (0.11
mmol), and 3 (0.10 mmol) was carried out in PhF (1.0 mL) at 10 °C for
3 d under Ar in the presence of gold catalyst (5 mol %), Brønsted acid
(10 mol %), and 4 A Ms (50 mg). b Combined yield of both diastereomers.
c The dr was determined by 1H NMR. d The ee was determined by
HPLC. e 5 mol % of 5g was used. f In PhBr (1.0 mL). g In 1,3-dichlor-
obenzene (1.0 mL). h In 1,2,4-trichlorobenzene (1.0 mL) at 15 °C. i The
compound details were described in the Supporting Information.
aromatic spiroacetals in up to 95% yield with >25:1 dr
and up to 91% ee (entries 1ꢀ7). A disubstituted salicylal-
dehyde with the chloro groups at both 4 and 6-positions
underwent the reaction to furnish the corresponding 4f in
81% yield and with 91% ee (entry 1). Notably, the position
of the substituent on the benzene ring of the salicylalde-
hydes exhibited significant effect on both the diastereo- and
enantioselectivities. For instance, 2-hydroxybenzalde-
hydes with a substituent at 4-postion gave higher enantios-
electivities than those with the substituent at either the
5- or 6-postion (entries 3, 6, and 7 vs 2 and 5). Excellent dia-
stereoselectivity (>25:1), together with a high yield (83%)
and high ee (85% ee), was obtained when 2-hydroxy-1-
naphthaldehyde was employed as a reaction component
(entry 4). Interestingly, the electron feature of the substi-
tuent on the benzene ring of 2-hydroxybenzaldehyde had
very little effect on the stereoselectivities (entries 3, 6, and 7).
Furtherinvestigation ofthe substrate scope wasfocusedon
the alkynols. Various alkynols with different aryl substi-
tuents, such as a 4-fluorophenyl and 4-bromophenyl group,
were tolerated. Excellent enantioselectivities were also
Under the optimal conditions, we next investigated the
generality for salicylaldehydes (Table 2). A wide range of
salicylaldehydes substituted with various substituents at
the benzene ring were applicable to the reaction, giving
(10) Salicylaldehydimines B can be easily afforded from the conden-
sation of 2 and 3 catalyzed by Brønsted acid, while in the absence of the
acid, the condensation will become very slow.
(11) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem., Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am.
Chem. Soc. 2004, 126, 5356. For reviews, see: (c) Akiyama, T. Chem. Rev.
2007, 107, 5744. (d) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107,
5713. (e) Terada, M. Chem. Commun. 2008, 4097. (f) Terada, M.
Synthesis 2010, 1929. (h) Rueping, M.; Lin, M. Y. Chem.;Eur. J.
2010, 16, 4169. (i) Bernardi, L.; Comes-Franchini, M.; Fochi, M.; Leo,
V.; Mazzanti, A.; Ricci, A. Adv. Synth. Catal. 2010, 352, 3399.
(12) For the use of fluorobenzene as the optimal solvent in gold/
Bronsted acid relay catalysis, see ref 8l.
Org. Lett., Vol. XX, No. XX, XXXX
C

on the benzene ring of alkynols also had considerable
influence on the reactivity. Thus, the alkynols with a
substituent at the 4-postion provided the corresponding
spiroacetals in excellent yield and enantioselectivities (up
to 97% yield and 95% ee). However, comparably lower
yields and enantioselectivities were obtained when 5-sub-
stituted alkynols were examined as substrates (entries
8ꢀ11 vs 12 and entries 13ꢀ16 vs 17). The configurations
of 4i were determined by X-ray crystallography analysis
(see the Supporting Information).
Table 2. Scope of Various Alkynols and Salicylaldehydes of the
Cascade Multiple Components Reactionsa
entry
4
R
R0
yieldb (%)
drc
eed (%)
1
2
4f
H
H
H
H
H
H
H
4,6-Cl2
5-Cl
81
79
70
83
95
78
87
91
75
71
72
67
87
92
83
97
62
94
87
88
10/1
>25/1
6/1
91
80
90
85
83
89
90
90
90
94
91
81
92
92
91
95
84
87
86
88
A scale-up three-component reaction 1a with 2-hydro-
xy-1-naphthaldehyde and 3e proceeded smoothly under
the catalysis of gold(I)/ Brønsted acid binary system to
generate the enantioenriched spiroacetal 4i in a maintained
yield and stereoselectivity. After recrystallization, the en-
antiomeric purity of 4i could be enhanced to >99% ee.
The hydrogenolysis of the optically pure 4i furnished 30H-
spiro[chroman-2,10-isobenzofuran] 6, which is presented
as the cyclic core unit in the natural product paecilospirone
(II),3b,c in 90% yield with 98% ee (see the Supporting
Information).
In summary, we have disclosed an asymmetric relay
catalytic multicomponent reaction by using gold(I) complex/
chiral phosphoric acid, which is able to assemble the
readily available and easily accessible substrates, including
salicylaldehydes, aniline, and alkynols into aromatic spir-
oacetals with high optical purity. The method provided an
important alternative of known methods to directly access
highly enantioenriched spiroacetals and would be poten-
tially applied to the synthesis of spiroacetal motifs pre-
sented in natural products.
4g
4h
4i
3
4-F
e
4
>25/1
9/1
5
4j
6-F
6
4k
4l
4-Br
6.5/1
4/1
7
4-Me
4,6-Cl2
4-F
8
4m
4n
4o
4p
4q
4r
4s
4t
4-F
>25/1
4.3/1
4.6/1
5/1
9
4-F
10
11
12
13
14
15
16
17
18
19
20
4-F
4- Br
4-Me
4,6-Cl2
4,6-Cl2
4-Me
4-F
4-F
5-F
>25/1
9/1
4-Cl
4-Cl
4-Cl
4-Cl
5-Cl
4-Me
4-Me
4-Me
4.3/1
4/1
4u
4v
4w
4x
4y
4-Br
4/1
4,6-Cl2
9/1
4,6-Cl2
e
>25/1
6/1
4-Br
3.5/1
a Unless indicated otherwise, the reaction of 1 (0.12 mmol), 2 (0.11
mmol), and 3e (0.10 mmol) was carried out in 1,2,4-trichlorobenzene
(1.0 mL) at 15 °C for 3 d under Ar in the presence of gold(I) catalyst
(5 mol %), Brønsted acid (10 mol %), and 4 A Ms (50 mg). b Combined
yield of both diastereomers. c The dr was determined by 1H NMR. d The
ee was determined by HPLC. e 2-Hydroxy-1-naphthaldehyde was used.
Acknowledgment. We are grateful for financial support
from NSFC (21232007), MOST (973 project 2010CB833300),
BASF, and the Ministry of Education.
obtained for those alkynols with different salicylalde-
hydes (Table 2, entries 8ꢀ20). Basically, the electron-
withdrawing substituent, such as either the fluoride,
chloride, or the bromide group, turned out to be bene-
ficial to the enantioselectivities, whereas the presence of
electron-donating substituents, such as the methyl group,
was slightly deleterious to the reactivity (entries 8ꢀ11 and
13ꢀ16 vs 18ꢀ20). Moreover, the position of the substituent
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. 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