Diastereoselective synthesis of optically active rotaxane amine N-oxides via through-space chirality transfer

Article abstract of DOI:10.1016/j.tetlet.2016.08.046

Selective synthesis of optically active rotaxane amine N-oxides was achieved with high diastereoselectivity via the effective through-space chirality transfer. Oxidation of tert-amine moiety on axle component of rotaxane with an optically active wheel com

Full text of DOI:10.1016/j.tetlet.2016.08.046

Tetrahedron Letters 57 (2016) 4356–4359
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Tetrahedron Letters
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Diastereoselective synthesis of optically active rotaxane amine
N-oxides via through-space chirality transfer
⇑
Kun Xu, Kazuko Nakazono, Toshikazu Takata
Department of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1, Ookayama, Meguro-ku, Tokyo 152-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Selective synthesis of optically active rotaxane amine N-oxides was achieved with high diastereoselectiv-
ity via the effective through-space chirality transfer. Oxidation of tert-amine moiety on axle component
of rotaxane with an optically active wheel component having (R)-binaphthyl group was carried out. The
oxidation of several rotaxanes with dimethyldioxirane was conducted in dichloromethane at ꢀ78 °C to
give the corresponding amine N-oxides with high diastereoselectivity up to 95%, indicating the conver-
sion via the effective through-space chirality transfer. Higher diastereoselectivity was observed with
the rotaxane possessing the rigid skeleton and the N-benzyl substituent. The optimized structures sug-
gested the stereochemistry of the nitrogen center of (R)-configuration.
Received 26 May 2016
Revised 6 August 2016
Accepted 17 August 2016
Available online 20 August 2016
Keywords:
Rotaxane
Chiral amine N-oxide
Through-space
Chirality transfer
Ó 2016 Elsevier Ltd. All rights reserved.
Introduction
of the axle component with a thiazolium salt moiety and the crown
ether wheel involving C2 chiral binaphthyl group.6
Chiral information transfer in supramolecular system has col-
lected much attention because of the dynamic nature and the
effective chirality transfer via through-space.1 Rotaxane character-
ized by the mechanically linked components can undertake the
through-space chirality transfer not only between the wheel and
axle components for chiroptical property2 but also between poly-
mer backbone and its pendant rotaxane units for the induction of
one-handed helix.3 Meanwhile, the use of rotaxanes as asymmetric
catalysts has been reported by controlling the dynamic nature of
the components.4 Nevertheless chiral rotaxane chemistry has been
progressed, the essential meaning of rotaxane structure for the
effective through-space chirality transfer has been little clarified
so far. We have studied mainly the effect of the chiral wheel com-
ponents on the rotaxane-related asymmetric reactions to find the
important structural factors. We first demonstrated an asymmetric
reaction through a Michael addition type end-cap reaction of a
bulky thiol to the methacrylate axle end of a pseudorotaxane hav-
ing chiral crown ether to prepare optically active rotaxane.5 The
through-space chirality transfer was certainly confirmed, although
the diastereoselectivity was only 6% de, which, however, was
Meanwhile, the modification of sec-ammonium function of
sec-ammonium/crown ether-type rotaxanes as most typical ones
seems a very important subject in the derivation and utilization
of rotaxanes, because these rotaxanes are synthesized using hydro-
gen bonding between sec-ammonium salt and crown ether, which,
however, is not necessary after the rotaxane formation. We have
recently found the direct conversion of sec-ammonium group to
tert-amine group as one of the modification methods.7 We focused
on the asymmetric oxidation of tert-amine moiety of rotaxane hav-
ing a chiral crown ether wheel via through-space chirality transfer.
Recently optically acitve amine N-oxides are used for catalytic
asymmetric allylation as a chiral ligand,8 whereas the control of
N-central chirality of amine N-oxide still remains much limitation
except for the case of neighboring chiral group-containing amines.9
This Letter deals with the diastereoselective synthesis of optically
active rotaxane amine N-oxides by direct oxidation of tert-amine
moiety of rotaxanes (Scheme 1).
Results and discussion
regarded relatively high as
a radical reaction involving the
Rotaxane substrates having tert-amine axle components and
(R)-benzo-1,10-binaphtho-26-crown-8-ether (BB26C8) 13a were
synthesized in two steps as shown in Scheme 2. A mixture of
sec-ammonium salt with a terminal OH group and (R)-BB26C8
was treated with a bulky benzoic acid in the presence of the
dehydrating agent (DIC) and base (tributylphosphine) to give
sec-ammonium/crown ether-type rotaxanes in 26–75% yields,
hydrogen abstraction as a key step for the stereogenic center
determination. Further, we reported the enantioselective benzoin
condensation (32% ee) with a chiral rotaxane catalyst consisting
⇑
Corresponding author. Tel.: +81 3 5734 2898.
E-mail address: ttakata@polymer.titech.ac.jp (T. Takata).
http://dx.doi.org/10.1016/j.tetlet.2016.08.046
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

K. Xu et al. / Tetrahedron Letters 57 (2016) 4356–4359
4357
Table 1
Oxidation of tert-amine (1a) to amine N-oxide (2a) under various conditions
Scheme 1. Diastereoselective oxidation of tert-amine to amine N-oxide of rotaxane
having a chiral wheel component.
Entry
Oxidizing agent (equiv)
Conditiona
Yield
(%)
deb
(%)
according to our previously reported method.7,10 Subsequent
reductive N-alkylation of sec-ammonium rotaxanes with an
appropriate aldehyde and sodium triacetoxyborohydride afforded
tert-amine-type rotaxanes (1a–1f) in 67–92% yields.7
1
2
3
4
5
6
7
mCPBA (10)
CHCl3, rt, 24 h
mCPBA (10)
0c
—
26
0c
19
—
Na2CO3 CHCl3, rt, 24 h
TBHP (20)
The oxidation condition was studied using rotaxane 1a at room
temperature (Table 1). With m-chloroperoxybenzoic acid
(mCPBA),11 no amine N-oxide (2a) was formed, probably due to
the acidification of the amine moiety (entry 1). To inhibit the
protonation of rotaxane substrate, the oxidation was conducted
under the presence of Na2CO3 to afford 2a in 26% yield (entry 2).
However the reaction with tert-butylhydroperoxide (TBHP) also
afforded no oxidation product (entry 3).11 A small amount of 2a
was obtained with hydrogen peroxide (entry 4). Addition of a
catalyst bis(acetyl acetonato)vanadium oxide (VO(acac)2) as a
typical catalyst (5 mol %) for TBHP enhanced the product yield to
22% (entry 5).12 The oxidation of 1a with dimethyl dioxirane
(DMDO) formed in situ in the presence of sodium carbonate was
carried out in dichloromethane to afford 2a in 98% yield as a highly
polar product (entry 6).13 Thus, the reaction with DMDO gave the
best result.
Na2CO3, tBuOH, rt, 24 h
H2O2 (10)
4.4
22
98
99
49
53d
49
79
Na2CO3, EtOAc, rt, 24 h
TBHP (20), VO(acac)2 (5 mol %)
Na2CO3, tBuOH, rt, 24 h
DMDO (10)
Na2CO3, CH2Cl2–H2O, rt, 12 h
DMDO (10)
Na2CO3, CH2Cl2–H2O, ꢀ78 °C, 12 h
a
[Substrates] = 0.1 mM (see SI, Scheme S2). Dimethyldioxirane (DMDO) was
generated in situ by the oxidation of acetone with oxone.
The de value was determined by chiral HPLC.
Protonated 1a was recovered.
Inverse stereochemistry at the nitrogen was confirmed.
b
c
d
The structure 2a was characterized by the appearance of a
strong IR absorption at ca. 1000 cmꢀ1 assignable to NAO bond
and a down field-shifted N-methyl proton signal (from 1.98 to
2.18 ppm) in the 1H NMR spectrum, in addition to the MALDI-
TOF MS spectrum with the molecular ion peak of 2a (see SI).
The diastereoselectivity was evaluated by chiral HPLC. The
oxidation of 1a with DMDO which gave the best chemical yield
resulted in the formation of optically active 2a with 49% de
(entry 6). Fortunately, the de highly increased up to 79% by employ-
ing the reaction at ꢀ78 °C (entry 7). Meanwhile, VO(acac)2-
catalyzed oxidation inverted the stereochemistry of the nitrogen
center. Although the stereoselection mechanism is not clear at pre-
sent time, we may presume that an attractive interaction between
the crown ether and VO(acac)2 regulates the through-space chirality
transfer from the wheel component as seen in the enhanced Cotton
effect in CD spectrum (SI, Fig. S24).
O
HO
O
O
O
O
O
O
O
O
R1
DIC, Bu3P
N
OH
+
H2
CH2Cl2, rt, 26–75%
PF6
The structure effect of the rotaxane substrate on the yield and
the de of the amine N-oxide was studied with the structure-
different rotaxanes prepared in Scheme 1. Under the optimized
conditions (DMDO, sodium carbonate, dichloromethane–water,
ꢀ78 °C, 12 h), all rotaxanes underwent the oxidation to give the
corresponding amine N-oxides in high chemical yields (80–99%)
(Table 2). Meanwhile, the de clearly depended on the rotaxane’s
structure as discussed below.
(R)-BB26C8
O
O
PF6
aldehyde
O
O
O
O
R1
NaBH(OAc)3,Et3N
N
O
tert-Amine-type
O
H2
rotaxanes
NMP, 80 °C, 67–92%
1a-f
O
O
The effect of the alkylene chain length of the axle component, or
the distance of the reaction center from the chiral crown ether
wheel, was investigated with 1a–1c. As the chain length increased,
the de value of 2a–2c clearly dropped, as expected, while the
chemical yield did not change. Since the crown ether wheel statis-
tically localizes around the ester group due to the weak CHAO
B B 26C8
O
O
N
CH3
O
N
O
H3C
hydrogen bonding with the
results can be reasonably explained.
a-proton to the ether oxygen, the
1c
1a
R2
The introduction of a p-phenylene moiety into the axle compo-
nent (1d) caused the great enhancement of the de value (2d, 79%,
Table 2) in comparison with that of 2b (33%, Table 2), although the
chemical yield was equally high. Since the length of the axle com-
ponent is similar, the remarkable increase would come from the
rigidity or the occupation of the wheel cavity, which makes effec-
tive through-space chirality transfer in the case of 1d, i.e., (i) the
H3C
1d
1e
1f
O
N
N
R2
O
H3C
O
O
1b
Scheme 2. Preparation of tert-amine-type rotaxanes 1.

4358
K. Xu et al. / Tetrahedron Letters 57 (2016) 4356–4359
Table 2
Synthesis of rotaxane amine N-oxides 2 by the oxidation
DMDO (10 equiv.)
tert-Amine-type rotaxane
N-Oxide-type rotaxane
1
2
Na2CO3, CH2Cl2–H2O
–78 °C,12 h
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
CH3
N
O
O
O
O
O
O
CH3
O
2a
99%, 79% de
2d 90%, 79% de
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
O
O
O
O
O
O
CH3
O
2b
85%, 33% de
2e
91%, 55% de
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
O
O
O
O
O
O
O
O
CH3
O
Δ|d1-d2|
d1(N–O1)
d2(N–O2)
yield /%
de /%
rotaxane
/Å
/Å
/Å
2c 80%, 12% de
2f 86%, 95% de
1d
1e
1f
90
91
86
79
55
95
5.94
6.58
4.96
6.97
6.31
5.86
1.03
0.27
0.90
interconversion of nitrogen center in 1d is presumably slower than
that in 1b by the effect of the rigid and heavy substituent so as to
fix the chirality of nitrogen center, (ii) the rigid conformation
enables the efficient through-space transfer of structural informa-
tion by limiting the conformation. Another explanation can be
obtained from Hirose’s report where the mobility of the wheel
component along the axle component is higher with the rigid axle
rather than the flexible one because of the fixed conformation
reduces the steric barrier for the mobility.14 Namely, rigid confor-
mation of rotaxane may affect the efficiency of the through-space
chirality transfer.
Furthermore, the effect of N-substituent on the axle component
was also investigated with 2d–2f (Table 2). The oxidation of 1d–1f
proceeded efficiently to give high yields over 80% of the corre-
sponding amine N-oxides (2d–2f). The lower yield of 2d–2f would
be the steric hindrance of the rigid structures comparing to 1a. The
most striking result is the very high de for 1f (95% de) in compar-
ison with those of 1d (79% de) and 1e (55% de). Thus, we could
synthesize optically active rotaxane amine N-oxide with excellent
de in a high yield. However, it is rather difficult to explain the
reason for such a high diastereoselectivity in the simple N-oxidation
of a tert-amine having N-benzyl group with DMDO without any
catalyst, we suggest the intervention of some special interaction
between the benzyl group and the chiral wheel component.
To evaluate the effect on the N-substituent, we compared the
optimized structures of 1d–1f (generated by Macromodel with
OPLS2005 force field, Fig. 1), because we could obtain no single
crystal suitable to X-ray analysis in all amine- and amine N-oxide
rotaxanes.
Calculated structures of 1d, 1e, and 1f were optimized at OPLS2005 force
field level by MacroModel.
Figure 1. Calculated structures of 1d, 1e, and 1f.
diastereoselectivity (Table 2), both d1 and d2 are larger than those
of 1d and 1f. Furthermore, the difference between d1 and d2 is
smaller than that of 1d and 1f. Therefore, the chiral wheel compo-
nent is kept away from the nitrogen moiety due to the bulkiness of
cyclohexyl group in 1e. The results of Table 2 and Figure 1 reveal
that both the oxidation and the through-space chirality transfer
are kinetically controlled in 1e.
On the other hand, the shorter distances d1 and d2 in 1f coin-
cides with the highest de. The d1 and d2 distances of 1f much
shorter than those of 1d must require other reason than the bulk-
iness of the N-substituent, because benzyl group (1f) is obviously
bulkier than methyl group (1d). At present time, we believe that
the p–p interaction between the benzyl group and the binaphthyl
group makes them nearer. As a result, the chirality transfer worked
much effectively in 1f among them, giving the 95% de. Since we
could not directly determine the stereochemistry of the major
products, the main stereochemistry of the nitrogen center was
assumed by the stereospecificity derived from the optimized struc-
tures. The optimized structures for 1d–1f took ‘S’ configuration for
the nitrogen center (Fig. 1), and thereby the product amine N-oxide
should take R-configuration when the oxidant approaches to the
O2 atom side. To generate (S)-N-oxide, the reaction should pass
the interconversion of nitrogen central chirality followed
by the rearrangement of the components. This is kinetically
disadvantageous process compared to the process for generation
of (R)-N-oxide. The improvement of de at lower temperature as
Distances between the nitrogen center on the axle and the oxy-
gen atoms of the crown ether wheel neighboring the binaphthyl
unit (O1 and O2) in the optimized structures were calculated as
the distance from the chiral center (d1 and d2), and are summa-
rized in Figure 1. From the distances in 1e which gave the lowest

K. Xu et al. / Tetrahedron Letters 57 (2016) 4356–4359
4359
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seen in entries 6 and 7 (Table 1) obviously supports that this reac-
tion proceeded under the kinetic control. Additional calculation of
both (S)- and (R)-amine N-oxides (2f) indicated (R)-conformer
takes a similar conformation to 1f rather than (S)-conformer,
suggesting the preferential formation of the rotaxane amine
N-oxide with (R)-configuration at the nitrogen center in thermody-
namic (SI, Figs. S1 and S2).
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Conclusion
In conclusion, we have succeeded in synthesizing optically
active rotaxane amine N-oxides in up to 95% diastereomeric excess
and up to 99% yield via the oxidation of the tert-amine moiety of
the axle component of the rotaxanes having a chiral crown ether
wheel via the effective through-space chirality transfer. From the
structural effect of the rotaxanes, it was concluded that not only
the distance between the reaction center and the chiral center
but also the axle rigidity as well as the presence of some
interactions between the components promote the efficient
through-space chirality transfer. We expect that this optically
active rotaxane amine N-oxides can be utilized as the unique chiral
sources.
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Acknowledgments
This research was financially supported by The Naito
Foundation and Grant-in-Aid for Challenging Exploratory Research
(15K13704).
Supplementary data
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Supplementary data (experimental procedures, spectra and
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