Synthesis of spiroaminals and spiroketals with bimetallic relay catalysis

Article abstract of DOI:10.1021/ol4033286

A novel tandem metal relay catalytic system was developed by combining gold-catalyzed cycloisomerization with an early transition-metal-catalyzed inverse-electron-demand hetero-Diels-Alder (IED-HDA) reaction. Various biologically important spiroaminals an

Full text of DOI:10.1021/ol4033286

Letter
pubs.acs.org/OrgLett
Synthesis of Spiroaminals and Spiroketals with Bimetallic Relay
Catalysis
Xianghua Wang, Shuli Dong, Zhili Yao, Lei Feng, Philias Daka, 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
‡
Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States
*
S Supporting Information
ABSTRACT: A novel tandem metal relay catalytic system was developed by combining gold-catalyzed cycloisomerization with
an early transition-metal-catalyzed inverse-electron-demand hetero-Diels−Alder (IED-HDA) reaction. Various biologically
important spiroaminals and spiroketals were obtained with very high efficiency under mild conditions.
n every complex molecule or natural product synthesis,
unstable, fragile, or arduously accessible subunits pose a
However, unlike spiroketals, the synthesis of spiro-N,O-aminals
has been much less explored. Very recently the Hashmi group
reported an efficient gold-catalyzed tandem reaction toward
I
challenge. Spiroketals and aminals are such structural units
1
10
which are widely present in many bioactive molecules.
tricyclic cagelike N,O-aminals. Many N,O-aminals containing
11a
11b,c
Spiroketal containing natural products are widely found in
insect pheromones, plants, bacterial, and marine sources. Many
molecules such as pederin, psymberin,
and aspidophy-
11d
tine showed important biological activities, thus the develop-
ment of an efficient synthetic methodology toward spiro-N,O-
aminals from readily available starting materials is in great
demand. Herein, we report a bimetallic gold/early transition
metal relay catalytic system for the synthesis of spiro-N,O-
aminals and spiroketals. This process exhibits very high
efficiency, high chemoselectivity and diastereoselectivity, and
high atom and step economy.
2
3
famous examples include okadaic acid, berkelic acid,
4
5
6
altohyrtin, aigialospirol, and avermectin (Figure 1). General
Earlier, we reported an efficient gold/Lewis acid relay
12
catalysis system toward fused bicyclic aminals by combining
1
3
14
π-acid gold catalysis with another σ metal Lewis acid. In this
12a
gold participating cascade reaction,
the alkyne amines 2
underwent a gold-catalyzed 5-exo-dig intramolecular hydro-
amination cyclization to afford the enamide M1, followed by
internal isomerization to enamide M2, and then reacted with
another Lewis acid activated electrophile 1 through HDA
Figure 1. Natural products containing spiroketals and spiro-N,O-
aminals.
15
reaction to produce the fused bicyclic aminals (Scheme 1).
Considering the biological and synthetic importance of
spiroaminals and spiroketals, we were interested in developing
an efficient method toward this type of molecules through
bimetallic catalysis. Unfortunately, all efforts to obtain the
spirocycle as the major product by fine-tuning the reaction
conditions were unsuccessful. We reasoned that to obtain the
spirocyclic product, the key issue is to inhibit the isomerization
reaction. We therefore replaced substrate 2 by alkyne amine 3,
in which two saturated carbons were replaced by a benzene
strategies to access this key motif are through Bronsted acid or
transition metal catalyzed intramolecular spiroacetalization of
prefunctionalized substrates. For example, the Aponick group
reported efficient gold- or palladium-catalyzed spiroketalization
7a,b
7d
reactions of monopropargylic triols or ketoallylic diols. List
7
e
and Nagorny independently reported enantioselective
spiroketalization of hydroxyalkyl-substituted enol ethers by
use of chiral phosphoric acid as the catalyst. Recently
8
Barluenga reported a palladium-catalyzed three-component
cascade reaction of salicylaldehyde for the synthesis of
spiroketals, and the Gong group developed the asymmetric
9
Received: September 30, 2013
reaction using metal/phosphoric acid combined catalysis.
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ol4033286 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Concept of the Bimetallic Lewis Acid Catalyzed
Cascade Reaction
Table 1. Optimization of Reaction Conditions
catalyst
b
entry
A
B
solvent
yield%
1
2
3
4
5
6
7
8
9
PPh AuNTf2
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
In(OTf)3
Ga(OTf)3
Sc(OTf)3
La(OTf)3
Bi(OTf)3
La(OTf)3
La(OTf)3
−
CH CN
71
3
3
IPrAuCl/AgOTf
CH CN
72
3
IMesAuCl/AgOTf
CH CN
46
3
AuCl·PPh /AgOTf
CH CN
64
3
3
AuCl(CH SCH )
CH CN
14
3
3
3
AgOTf
CH CN
0
3
IPrAuCl/AgSbF6
IPrAuCl/AgNTf2
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
−
CH CN
64
3
CH CN
57
3
CH CN
41
3
1
1
1
0
1
2
CH CN
37
3
CH CN
37
3
CH CN
90
3
ring. In this way, the inward isomerization of the generated
enamide T1 is blocked, thus making it possible to react with
activated electrophiles to generate spirocyclic products
13
14
15
16
17
CH CN
messy
<10
<10
trace
0
3
CH Cl
2
2
toluene
(
Scheme 1).
CH CN
3
To test this hypothesis, alkyne 3 and unsaturated keto-ester
La(OTf)3
CH CN
3
1
a were subjected to this cascade reaction in the presence of
a
Reaction conditions: 3 (0.1 mmol), 1a (0.12 mmol), catalyst A (5
b
(
(
PPh )AuNTf and Y(OTf) in CH CN at room temperature
Scheme 2). It turned out to be a very messy reaction mixture.
3
2
3
3
mol %), catalyst B (10 mol %), solvent (1 mL) at 0 °C. Isolated yield.
La(OTf) was the best choice, and the target spiro-aminal 4a
was isolated in 90% yield. Control experiments confirmed that
3
Scheme 2. Initial Formation of the Spiro-N,O-Aminal
both the gold catalyst and La(OTf) are necessary in this
3
process (entries 16, 17). Without the early transition metal, a
very messy reaction was observed; only a trace amount of the
product was detected on TLC, and no product was formed
without the gold catalyst.
With the optimized conditions established, the substrate
scope was next examined (Scheme 3). The β,γ- unsaturated-α-
keto-esters with different aromatic substituents at the γ-position
Scheme 3. Scope of the Au(I)−La(III) Catalyzed Cascade
a
Reaction for Synthesis of Spiro-aminals
To our delight, when we lowered the reaction temperature to 0
°
C, the target spiro-N,O-aminal 4a was isolated in 71% yield.
The structure and stereochemistry were unambiguously
characterized by NMR, mass spectrometry, and single X-ray
crystallography. Remarkably, the diastereoselectivity was very
good and only single endodiastereomer was detected in this
reaction, which agrees well with the proposed transition state in
Scheme 1.
Encouraged by these results, we continued to optimize the
reaction conditions to develop an efficient bimetallic Lewis acid
catalyzed system toward spiro aminals (Table 1). A series of
different gold catalysts were examined (entries 1−5), and it was
found that the combination of an NHC carbene ligated gold
catalyst with AgOTf afforded the product in the highest yield
(
72%, entry 2). Other commonly used gold catalysts such as
AuCl·PPh /AgOTf, IMesAuCl/AgOTf, AuCl(CH SCH ),
3
3
3
AuCl, and AuCl resulted in lower yields (see Supporting
3
Information). Different counterions were also explored and
could not give better results (entry 2 vs entries 7, 8). Then we
investigated different early transition metals such as In(OTf)3,
Ga(OTf) , Sc(OTf) , La(OTf) , and Bi(OTf) together with
a
3
3
3
3
Reaction conditions: 3 (0.2 mmol), 1 (0.24 mmol), IPrAuCl/AgOTf
the optimal gold catalyst (entries 9−13). Among all of them,
(5 mol %), La(OTf) (10 mol %), CH CN (2 mL) at 0 °C for 1 h.
3
3
B
dx.doi.org/10.1021/ol4033286 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reacted smoothly with alkyne amine 3 to give the spiro-N,O-
aminal 4 in good to excellent yields in less than 1 h. The
diastereoselectivity was very good in all these reactions, and
only the endo isomers were detected. Different ester groups
and halogen groups at the para or ortho position of the phenyl
ring did not affect the reaction (4a−4f). Substrates bearing an
electron-donating group such as methyl and methoxyl were also
suitable substrates, giving the corresponding spiro-aminals in
Scheme 5. Cascade or Stepwise Reaction of the Internal
Alkyne
8
7% and 76% yield respectively (4g, 4h). In addition, more
sensitive substituents such as styryl, 2-furyl, and 2-thienyl were
well tolerated in this mild transformation and the correspond-
ing products were obtained in 71−80% yields (4i, 4j, 4l).
By simply switching the nucleophilic nitrogen to oxygen in
substrate 3, we are able to obtain spiroketals instead following
this strategy. Through optimization, the desired spiroketal 6a
gold/Lewis acid relay catalysis. The features of this protocol
include very high efficiency, excellent diastereoselectivity, 100%
atom economy, and simple one-pot operation which does not
require an inert atmosphere. Application of this bimetallic
strategy to other reactions is underway in our laboratory.
could be obtained in 90% yield in the presence of PPh AuNTf2
3
(
5 mol %) and Y(OTf) (10 mol %) in acetonitrile at rt. If the
3
La(OTf)3 (the optimal Lewis acid for nitrogen-based
substrates) was used, a slightly lower yield (71%) was obtained
(
for details, see Supporting Information). A series of
unsaturated keto-esters were also subjected to these reaction
conditions and gave the corresponding spiroketal in very good
yields (82−91%) in 1 h (Scheme 4). The diastereoselectivities
ASSOCIATED CONTENT
Supporting Information
■
*
S
Experimental procedures, characterization data, and NMR
spectra for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Scheme 4. Scope of the Au(I)−Y(III) Catalyzed Cascade
a
Reaction for Synthesis of Spiroketals
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: Xuzh@sdu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the Natural Science
Foundation of China and Shandong Province (Grant Nos.
■
2
1102085, BS2012-YY006), Science Foundation of Ministry of
Education of China (No. 20110131120049), and Shandong
Univerisity.
a
Reaction conditions: 5a (0.2 mmol), 1 (0.24 mmol), PPh AuNTf (5
3
2
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■
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