Catalytic asymmetric iodocyclization of N-tosyl alkenamides using aminoiminophenoxy copper carboxylate: A concise synthesis of chiral 8-oxa-6-azabicyclo[3.2.1]octanes

Article abstract of DOI:10.1002/anie.201505748

A newly developed aminoiminophenoxy copper carboxylate (L7-Cu-OAc)-catalyzed asymmetric iodocyclization of N-Tosyl alkenamides gave O-cyclized products in good yields with high enantioselectivity. From the O-cyclized products, a skeletal transformation was succeeded in the synthesis of biologically important chiral 8-oxa-6-azabicyclo[3.2.1]octanes. DFT calculations suggested that the acetoxy anion of the [L7-Cu-OAc] acts as a base to generate the anion of N-Tosyl alkenamide substrates. The exchanged acetic acid reconstructs a new hydrogen-bonding network between the catalyst and the substrates to accomplish the highly efficient asymmetric O-iodocyclization of N-Tosyl alkenamides. An aminoiminophenoxy copper carboxylate-catalyzed asymmetric iodocyclization of N-Tosyl alkenamides gave O-cyclized products in good yields with high enantioselectivity. Chiral 8-oxa-6-azabicyclo[3.2.1]octanes were synthesized by a sequential reduction/cyclization process from the iodocyclization product. DFT calculations suggested that the N-tosyl alkenamides are activated by hydrogen bonding with a carboxylate anion on the copper center to allow iodo-O-cyclization.

Full text of DOI:10.1002/anie.201505748

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201505748
German Edition: DOI: 10.1002/ange.201505748
Aymmetric Iodocyclization
Catalytic Asymmetric Iodocyclization of N-Tosyl Alkenamides using
Aminoiminophenoxy Copper Carboxylate: A Concise Synthesis of
Chiral 8-Oxa-6-Azabicyclo[3.2.1]octanes
Takayoshi Arai,* Ohji Watanabe, Shinnosuke Yabe, and Masahiro Yamanaka
Abstract: A newly developed aminoiminophenoxy copper
carboxylate (L7-Cu-OAc)-catalyzed asymmetric iodocycliza-
tion of N-Tosyl alkenamides gave O-cyclized products in good
yields with high enantioselectivity. From the O-cyclized
products, a skeletal transformation was succeeded in the
synthesis of biologically important chiral 8-oxa-6-azabicyclo-
The next important step for these fundamentally important
catalytic asymmetric iodocyclization reactions is their appli-
cation in conjunction with synthetically useful transforma-
tions. Herein, we report a catalytic asymmetric iodocycliza-
tion of N-Tosyl alkenamides using a newly developed simple
aminoiminophenoxy copper carboxylate complex, and a fur-
ther concise transformation to the give, significantly, chiral 8-
oxa-6-azabicyclo[3.2.1]octanes.
Based on the success of our investigation of catalytic
asymmetric iodolactonization, alkenamides were used as
reaction substrates in this study (Table 1). Although the
primary amide showed low reactivity (entry 1), the N-Tosyl
[
8]
[
3.2.1]octanes. DFT calculations suggested that the acetoxy
anion of the [L7-Cu-OAc] acts as a base to generate the anion
of N-Tosyl alkenamide substrates. The exchanged acetic acid
reconstructs a new hydrogen-bonding network between the
catalyst and the substrates to accomplish the highly efficient
asymmetric O-iodocyclization of N-Tosyl alkenamides.
C
hiral iodine-functionalized compounds, which have unique
[a]
Table 1: Development of a catalyst for iodocyclization of alkenamides.
properties, are used for various purposes in material and
[
1]
pharmaceutical science. Stereoselective iodocyclization is
a powerful synthetic tool for generating iodine-functionalized
cyclic compounds, and this has been widely applied using
chiral substrates and in the total synthesis of natural products.
Because of their importance, the development of catalytic
asymmetric iodocyclization reactions has received much
[
2]
attention in the last decades. In 1995, Taguchi and co-
workers reported an example of enantioselective iodocarbo-
cyclization of 4-alkenylmalonates using chiral titanium alk-
[
3]
oxide. Phosphoramidite-promoted enantioselective iodo-
cyclization of polyprenoids, developed by Ishihara and co-
workers, has been a subject of investigation with the aim of
[
4a]
developing a catalytic system. Kang et al. reported a cata-
lytic asymmetric iodoetherification reaction using a chiral
Entry
R
L
M
x
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
H
Ac
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
Zn
Zn
Zn
Cu
Cu
Cu
Ni
30
30
30
30
20
10
30
20
30
20
10
10
10
10
10
10
10
10
10
10
trace
trace
50
80
59
58
75
trace
80
50
78
63
54
68
86
88
52
80
–
–
19
6
61
58
23
–
33
19
49
9
43
65
89
93
85
81
87
85
II
[4b]
salen–Co complex. After Jacobsenꢀs pioneering work on
efficient urea-catalyzed asymmetric iodolactonization, sev-
[5a]
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
[
5]
eral successful lactonization reactions and related catalytic
[
6]
asymmetric iodocyclizations using organocatalysts have
been reported. We reported a catalytic asymmetric iodolac-
tonization reaction using an originally developed trinuclear
[
7]
Ni
[
Zn (OAc) {3,3’-bis(aminoimino)binaphthoxide}] catalyst.
3 4
Co
Co
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
1
0
[
*] Prof. Dr. T. Arai, O. Watanabe
Molecular Chirality Research Center,
Synthetic Organic Chemistry, Department of Chemistry,
Graduate School of Science,
11
12
13
14
15
16
17
Chiba University
1
E-mail: tarai@faculty.chiba-u.jp
-33 Yayoi, Inage, Chiba 263-8522 (Japan)
1
1
2
8
9
0
S. Yabe, Prof. Dr. M. Yamanaka
Department of Chemistry,
Rikkyo University
91
98
3
-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501 (Japan)
[
a] Absolute configurations were determined based on hydrolysis of the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505748.
Tosyl-imine portion of the products by introducing the relevant
iodolactones.
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alkenamide (1a), which contains a more acidic amide proton,
was catalyzed by [Zn (OAc) {3,3’-bis(aminoimino)binaphth-
planar phenoxide complex in which the isoindoline ring
stands perpendicular to the copper-containing square planar
structure. This isolated crystal was actually catalytically
active, giving 2a in 98% yield with 93% ee.
Using the isolated [L7-Cu-OAc] complex in powder form
as a catalyst, we investigated the generality of [L7-Cu-OAc]-
catalyzed iodocyclization reactions in Table 2 (see details of
the isolation of the powder catalyst in the Supporting
Information).
3
4
oxide}] to give the O-cyclized product in 50% yield with 19%
[
9]
ee (entry 3). This was in contrast to the N-cyclized products
[10,11]
obtained using alkenoic amide substrates.
Among the metal salts examined in conjunction with 3,3’-
bis(aminoimino)binaphthol, the {Cu(OAc) } complex showed
2
better catalytic activity than the original zinc complex
(
entry 4). For the {Cu(OAc) } complex, reinvestigation of
2
the ratio of metal salt to ligand revealed that the catalyst
prepared with a ratio of 1:2 gave the product in 61% ee
For the R-group of the alkeneamide substrate 2, various
aromatic substituents were successfully employed, and ali-
phatic substituents were also used in highly enantioselective
iodocyclization reactions. The simple and stable nature of
[L7-Cu-OAc] confirms the practical usefulness, and the
reaction can be conducted in 5 mol% for the gram scale
synthesis of 2a (98%, 93% ee).
The (Z)-Tosyl-imine structure of the O-cyclized product
was confirmed by X-ray crystallographic analysis of rac-2k
(Figure 2). In the structure, halogen bonding between the
oxygen atom of the sulfonyl group and the iodine atom
(3.871 Š) was thought to contribute to stabilization of the
(Z)-form of Tosy-limines.
(
entry 5). ESI-MS analysis of the catalyst solution prepared
by mixing L1 and {Cu(OAc) } in a 1:2 ratio revealed
2
a significant ion peak at m/z = 1300.2349, attributed to the
+
trinuclear [L1-Cu (OAc) ] , as well as the desired ion peak at
3
3
m/z = 1119.2821, corresponding to the dinuclear [L1-Cu -
2
+
(
(
OAc)] . Based on the formation of the trinuclear [Zn -
3
OAc) {3,3’-bis(aminoimino)binaphthoxide}] complex, it is
4
thought that the third copper cation bridges the two naphthol
oxygen atoms, making a binaphthoxide. Use of the trinuclear
complex as a catalyst resulted in the production of 2a with low
ee in this case, although the catalytic activity was quite high.
To avoid the incorporation of supernumerary copper salts in
the catalyst, salicylaldehyde-derived aminoiminophenol
ligands (L2–L11), containing a single phenol unit, were
examined (entries 11–20). The rather simple [L2-Cu(OAc)2]
The utility of the iodocyclization products were demon-
strated by a transformation to a chiral 8-oxa-6-azabicyclo-
[3.2.1]octane skeleton, which has been reported as an
antiosteoporotic agent and an antimicrobial agent
[12]
complex, prepared by mixing L2 and Cu(OAc) in a 1:1 ratio,
(Figure 3).
2
smoothly catalyzed the reaction to give the product with
moderate stereoselectivity of 49% ee (entry 11). The use of
ortho-substituted salicylaldehyde was effective in improving
the enantioselectivity, and the 3,5-dibromosalicylaldehyde-
Table 2: [L7-Cu-OAc]-catalyzed iodocyclization of N-Tosyl alkenamides.
derived aminoiminophenol [L7-Cu(OAc) ] complex suc-
2
ceeded in giving the product in 88% yield with 93% ee
(
entry 16). The 3,5-dichlorosalicylaldehyde-derived amino-
iminophenol (L10) and the 3,5-diiodo derivative (L11) were
also effective for the copper-catalyzed iodocyclization to give
2
a with 87% ee and 85% ee, respectively (entries 19 and 20).
Fortunately, the [L7-Cu(OAc) ] complex was easily crys-
2
talized from ethanol, and the structure was revealed as the
aminoiminophenoxy copper(II) acetate complex [L7-Cu-
OAc] by X-ray crystallographic analysis (Figure 1). With the
remaining acetoxy anion included on the copper center,
bidentate coordination of chiral diamines provides a square
[
a] Reaction was conducted for 40 h. [b] ee was determined after
Figure 1. X-ray crystallographic analysis of the aminoiminophenoxy
copper(II) acetate complex [L7-Cu-OAc]. Ellipsoids set at 50% proba-
bility. CCDC 1061958.
transformation to the reported iodolactone by hydrolysis of the Tosyl-
imine portion. [c] NBS (1.1 equiv) and Br (0.2 equiv) were used.
[
16]
2
1
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[a]
Table 3: Asymmetric synthesis of 8-oxa-6-azabicyclo[3.2.1]octane.
Figure 2. X-ray crystallographic analysis of rac-2k. Ellipsoids set at 50%
[
16]
probability. CCDC 1061959.
[
a] Value in parentheses is ee of 2. [b] Reduction was conducted at
À408C.
Figure 3. Biologically significant chiral 8-oxa-6-azabicyclo[3.2.1]octanes.
After reduction of the iodocyclization products using
DIBAL-H at 08C for 15 min, further treatment with K CO3
2
furnished chiral 8-oxa-6-azabicyclo[3.2.1]octane skeletons
(
Table 3). Because the generated intermediate Tosyl-aminal
is easily epimerized at the anomeric position, regardless of the
stereoselectivity of the first reduction, the 8-oxa-6-azabicyclo-
Scheme 1. Removal of the Tosyl-group from 8-oxa-6-azabicyclo-
[3.2.1]octane (4a).
[
3.2.1]octane skeletons were obtained in high yields, retaining
the enantiomeric excesses. Furthermore, from 93% ee of 4a,
the Tosyl-group was successfully removed by Mg in MeOH to
give 93% ee of 5a in 97% yield (Scheme 1).
Based on the experimental analysis of the interaction of
[L7-Cu-OAc] with 1a, DFT calculations (UB3LYP) were
carried out for the transition state (TS) of the [L10-Cu-OAc]-
[13]
With regard to the mechanism of asymmetric iodocycli-
zation, the reaction is believed to start with activation of the
N-Tosyl alkenamide by the [L7-Cu-OAc] complex. ESI-MS
analysis of a mixture of N-Tosyl alkenamide 1a with [L7-Cu-
OAc] showed an ion peak at m/z = 1001.0529, corresponding
to the formation of [L7-Cu(TsN(C=O)(CH ) C(CH )Ph +
[
14]
catalyzed iodocyclization reaction.
Initial screening of
various activation modes and conformational isomers for
the associative TS models indicated that the acetoxy anion
(pK = 4.76) of the [L10-Cu-OAc] complex acts as a base to
a
generate the anion of 1a, as expected from the ESI-MS
analysis (Figure 4). Although TS0 is the spontaneous CÀO
2
3
2
+
Na] . However, the acidity of the carboxylic acid utilized in
the L7-Cu complex formation influenced the catalytic activity.
bond forming process after the event of deprotonation from
1a, energetically more favored TS1 is found by a reconstruc-
tion of the hydrogen bonding network between the catalyst
[
L7-Cu-benzoate] (pK of benzoic acid = 4.19) gave 2a in
a
9
8% yield with 93% ee (À788C, 14 h). [L7-Cu-p-methox-
[15]
ybenzoate] (pK of p-methoxybenzoic acid = 4.46) showed
and the substrate. In the TS1, the two oxygen atoms of the
sulfonyl group coordinate to the copper center and the acetic
acid. The simple dissociation of the acetic acid (TSX in
Figure 4) was not supported by the DFT calculations or the
experimental results.
a
higher catalytic activity, giving 2a in 99% yield with 94% ee
(
À788C, 6 h), whereas [L7-Cu-p-nitrobenzoate] (pK of p-
a
nitrobenzoic acid = 3.41) required a longer reaction time to
give 2a in 92% yield with 90% ee (À788C, 24 h). These
results suggest that the acetoxy anion in the [L7-Cu-OAc]
catalyst is not simply exchanged with the N-Tosyl alkenamide
To clarify the major factor in the high enantioselectivity of
the reaction, diastereomeric TSs leading to the major (TSr1)
and minor (TSs1) products were compared (Figure 5). The CÀ
1
a.
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L10 through hydrogen bonding. Aminoiminophenol derived
from the electron-deficient salicylaldehyde enhances the
acidity of the H atoms of the imino group to promote
coordination of NIS, resulting in higher enantioselectivity. In
contrast, the sterically demanding tBu group interferes with
coordination of NIS to cause a significant decrease in
enantioselectivity. Control experiments with respect to the
iodine source also strongly emphasized the contribution of
NIS coordination to TS stabilization. The addition of I was
2
Figure 4. Representations of the predicted TS models (TS0, TS1, and
TSX).
important for accelerating the [L7-Cu-OAc]-catalyzed iodo-
[
4b, 5a,c,h,6d,f, 7]
cyclization.
2
Without I , the reaction at À408C gave
2
a in 61% yield with 73% ee, although the iodocyclization did
not proceed at À788C under a similar conditions of Table 2. In
TSs1-a, leading to reversed facial selectivity in the iodocyc-
lization, conformational change of the anion of 1a has no
impact on the steric interaction between the catalyst and the
substrate. However, NIS has no effective hydrogen bond with
the catalyst moiety to destabilize TSs1-a. In TSs1-b, the anion
of 1a is located on the opposite side of the square planar unit
of the catalyst, while the hydrogen bonds between NIS and
the imino group of L10 are maintained. Steric repulsion
between the N-Tosyl group of 1a and the isoindoline ring of
L10 destabilizes TSs1-b. Therefore, TSs1-a and TSs1-b are 2.6
À1
and 1.0 kcalmol less stable than TSr1-a, respectively. These
TS models provide a reasonable explanation for the forma-
tion of the (R)-enriched product using the (R,R)-diphenyle-
thylenediamine-derived [L10-Cu-OAc] catalyst.
In conclusion, a newly developed aminoiminophenoxy
copper carboxylate complex was found to catalyze asymmet-
ric iodocyclization of N-Tosyl alkenamides to give the
products in an O-selective cyclization manner in good yield
and with high enantioselectivity. From the products, efficient
synthesis of chiral 8-oxa-6-azabicyclo[3.2.1]octanes was ach-
ieved. DFT calculations suggested a unique role of the
counteranion for activating the reaction substrates.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysts” from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan, and by
the Workshop on Chirality at Chiba University (WCCU).
Keywords: asymmetric catalysis · copper · cyclization ·
DFT calculations · halogenation
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12767–12771
Angew. Chem. 2015, 127, 12958–12962
Figure 5. 3D structures, representations, and relative energies of
diastereomeric TSs (TSr1-a, TSs1-a, and TSs1-b). Bond lengths are
shown in Š.
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[15] Details of the initial screening of conformational isomers in TS0
and TS1 are shown in Supporting Information.
[
[
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[16] CCDC 1061958, 1061959, and 1061961 contain the supplemen-
tary crystallographic data for this paper. These data are provided
free of charge by The Cambridge Crystallographic Data Centre.
[
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Received: June 22, 2015
Revised: July 24, 2015
Published online: September 14, 2015
Angew. Chem. Int. Ed. 2015, 54, 12767 –12771
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12771