Intramolecular (4?+?3) cycloadditions of nitrogen-tethered epoxy enosilanes for the synthesis of heteropolycycles

Article abstract of DOI:10.1016/j.cclet.2019.04.051

Furans bearing epoxy enolsilane units via a tether that incorporates a nitrogen heteroatom, undergo intramolecular (4 + 3) cycloadditions to generate bis-heteroatomic polycyclic adducts having piperidine moieties in their frameworks. The cycloadducts, ultimately derived from furfural, a renewal chemical feedstock, are obtained with up to 4:1 dr and with ee retained from the epoxide.

Full text of DOI:10.1016/j.cclet.2019.04.051

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CCLET 4944 No. of Pages 4
Chinese Chemical Letters xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Intramolecular (4 + 3) cycloadditions of nitrogen-tethered epoxy
enosilanes for the synthesis of heteropolycycles
Jiayun Hea, Shuk Mei Lama, Jerome P.L. Nga, Wing-Tak Wongb, Pauline Chiua,
*
a
State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China
b
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Available online xxx
Furans bearing epoxy enolsilane units via a tether that incorporates a nitrogen heteroatom, undergo
intramolecular (4 + 3) cycloadditions to generate bis-heteroatomic polycyclic adducts having piperidine
moieties in their frameworks. The cycloadducts, ultimately derived from furfural, a renewal chemical
feedstock, are obtained with up to 4:1 dr and with ee retained from the epoxide.
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Heterocycles
(4 + 3) cycloaddition
Furan
Intramolecular
Epoxides
Piperidine
Polycyclic compounds
Heterocycles feature prominently in many molecules of
importance in biological, agricultural and medicinal chemistry
[1–7]. Often, more than one heteroatomÀÀthe most common of
them being oxygen and/or nitrogenÀÀare found in such hetero-
cycles. The substitution pattern, ring size, and stereochemistry of
heterocyclic moieties in these compounds are varied, and hence
new synthetic strategies, particularly those based on green starting
materials and methods, are desirable for obtaining these hetero-
cycles.
heteroatomic features for constructing more complex heterocyclic
frameworks. We also noted that these heteroatom-tethered
cycloaddition substrates 8a-c can be obtained from furfural 7, a
compound currently being produced at about 280 kTon annually
from lignocellulosic biomass [11], making this strategy a more
green synthesis of hetero-polycycles. As a proof of concept, we
explored the synthesis of several nitrogen-tethered furan sub-
strates, and examined their cycloadditions for the green synthesis
of bis-heteroatomic tricyclic adducts.
We have been studying both the inter- (Scheme 1) and
intramolecular (4 + 3) cycloadditions (Scheme 2) of epoxy enolsi-
lanes with furan that proceeded under silyl triflate catalysis [8].
While the intermolecular cycloaddition proceeded without dia-
stereoselectivity to generate both the endo 2 and the exo 3
cycloadducts, the intramolecular (4 + 3) cycloaddition of 4 was
highly endo selective to provide polycylic adduct 5. The oxabicyclic
or oxatricyclic adducts 2, 3, 5 have been obtained with highly
conserved ee from enantiomerically enriched epoxides [9], and this
has been attributed to the stereochemically-defined, activated
epoxides, rather than the achiral oxyallyl cations, that are the
electrophilic species undergoing cycloaddition [10].
To explore the feasibility of a synthesis of these nitrogen-
containing heterocycles from a (4 + 3) cycloaddition strategy,
substrates 8a-c were designed that join the furan to the epoxy
enolsilane moiety by a tether bearing nitrogen. Cycloaddition
substrates 8a-c were synthesized as shown in Scheme 3 from
furfural 7, an abundant starting material. Reductive amination with
allylamine afforded amine 9 [12], which was N-protected using
three different protecting groups to give allylic amines 10a-c. Each
of these were homologated by cross-metathesis with methyl vinyl
ketone to provide 11a-c. Racemic epoxy ketones 12a-c were
obtained by nucleophilic epoxidation. Asymmetric epoxidation
under Deng’s conditions [13] provided epoxyketone (À)-12a in 83%
ee after recrystallization. Deprotonation and silylation afforded
cycloaddition substrates 8a-c (for details refer to the Supporting
Information).
To further explore the scope of the (4 + 3) cycloadditions, we
aimed to explore intramolecular cycloaddition substrates which
bear
a heteroatom-containing tether, to install additional
Under the typical reaction conditions using a catalytic amount
of TESOTf at low temperatures, (4 + 3) cycloaddition of 8a
proceeded, and provided cycloadducts 17a and 18a bearing
piperidine-fused frameworks, with 17a being the major
* Corresponding author.
E-mail address: pchiu@hku.hk (P. Chiu).
https://doi.org/10.1016/j.cclet.2019.04.051
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: J. He, et al., Intramolecular (4 + 3) cycloadditions of nitrogen-tethered epoxy enosilanes for the synthesis of
heteropolycycles, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.04.051

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reactivity or the outcome of the cycloaddition reaction, yet this was
not the case. Although 8a reacted under similar conditions as in the
cycloaddition of 4 having an all-carbon tether (Table 1, entries 1–
2), the cycloaddition of substrate 8b bearing a less electron-
withdrawing carbamate protecting group was largely incomplete
using a catalytic amount of TESOTf (Table 1, entry 3). A large
amount of the desilylated substrate 12b was recovered after
workup. Ultimately, a stoichiometric amount of TESOTf was
required for full conversion (Table 1, entry 4). We surmised that
the Lewis basic heteroatoms in the tether of 8b could be
sequestering the silyl triflate, making it less available for inducing
cycloaddition. Using TfOH as a catalyst [14] did not improve the
cycloaddition results (Table 1, entry 5). Observations were similar
for the CBz-protected substrate 8c (Table 1, entry 6).
Scheme 1. Intermolecular (4 + 3) cycloadditions of an epoxy enolsilane with furan.
In addition, diminished cycloaddition yields were observed in
the reactions of 8b and 8c compared with 8a: this was because
Scheme 2. Intramolecular (4 + 3) cycloadditions of an epoxy enolsilane with furan.
Scheme 3. Synthesis of cycloaddition substrates 8a-c.
Table 1
Intramolecular (4 + 3) cycloadditions of epoxy enolsilanes with furans
.
Entry
Substrate
X
TESOTf (equiv.)
Yield (17+18)a
dr (17:18)b
Recovered (%)
1
2
3
4
5
6
4
CH2
NTs
NCO2Me
NCO2Me
NCO2Me
NCBz
0.1
0.2
0.1
1.2
0.6d
1.2
83% [1]
67%
(only 5)
4.0:1
1.2:1
1.2:1
1:1
–
8a
8b
8b
8b
8c
12a (6)
12b (77)
12b (5)
12b (16)
12c (12)
11%
56%c
33%
50%c
1.8:1
a
Isolated yields of both cycloadducts.
b
c
All dr ratios were determined from the 1H NMR spectrum of the crude product mixture.
Side product 19 was observed.
d
TfOH used instead of TESOTf.
diastereomer (Table 1, entry 2, for details refer to the Supporting
Information). The structures and relative stereochemistries of
cycloadducts 17a and 18a were determined to be derived from
endo and exo cycloadditions respectively, deduced based on NOE
experiments as shown in Scheme 4.
Moreover, the (4 + 3) cycloaddition of (+)-8a of 83% ee generated
(À)-17a and (+)-18a of 86% ee and 84% ee, respectively. The X-ray
crystallographic analysis of (À)-17a confirmed its absolute
stereochemistry to be as shown (Flack parameter = 0.11). These
results showed that the intramolecular cycloaddition also pro-
ceeded, not by an oxyallylic cation, but via the intermediacy of an
activated epoxide that directed backside attack and whose
absolute stereochemistry directed the cycloaddition.
both reactions were further complicated by the generation of cyclic
carbamate side product 19, which was isolated in 5% and 12% yields
respectively. This side product was deduced to arise, as shown in
Scheme 5, from the attack of the activated epoxide by the
carbamate protecting group that consumed some of the starting
materials 8b and 8c.
The diastereoselectivities of these cycloadditions were also
lower than expected. In contrast to the exclusive endo-selectivity in
the cycloaddition of 4 (Table 1, entry 1), the reaction of 8a
generated endo- and exo-diastereomers 17a and 18a with dr = 4.0:1.
The reactions of 8b and 8c produced piperidine-fused heterocyclic
adducts 17b/c and 18b/c, but the endo/exo selectivities were even
lower (Table 1, entries 4, 6).
At the start, it may be presumed that the introduction of a
heteroatom into the tether of an intramolecular (4 + 3) cycloaddi-
tion substrate would not lead to any remarkable differences in the
The stereoselective synthesis of bis-heteroatomic polycyclic
adducts using this (4 + 3) cycloaddition route was more challenging
than expected. The presence of an amine group in the tethers of the
Please cite this article in press as: J. He, et al., Intramolecular (4 + 3) cycloadditions of nitrogen-tethered epoxy enosilanes for the synthesis of
heteropolycycles, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.04.051

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3
intramolecular (4 + 3) cycloaddition substrates was not initially
anticipated to induce significant effects on the cycloaddition
compared with the reaction of 4, as computational and experi-
mental studies on an intramolecular Diels-Alder reaction showed
that the effects of a heteroatom-containing tether compared with
an all-carbon linkage was negligible [15]. From the start, the
heteroatom tether necessitated reaction conditions with a higher
concentration of Lewis acid. We surmise that the heteroatom effect
was not likely to be steric in origin. In fact, transition state 19a
resulting in the endo cycloadduct has typically been the more
favoured, as there is better alignment of the atoms undergoing
cycloaddition compared with 20a (Scheme 6). It is not obvious how
heteroatoms replacing the carbon at the C2 position, as typified by
substrate 8b in Scheme 6, would significantly sterically alter the
stability of 19b relative to 20b. We conjecture that the effect may
be electronic, and one possibility may be that additional
association of the protected amine group with the silylating agent
could lead to a pre-organization of substrate 8b which favoured
20c. However, computations will be needed to elucidate with more
certainty the factors at play.
Scheme 4. Intramolecular (4 + 3) cycloaddition of epoxy enolsilane (+)-8a.
Scheme 5. Proposed mechanism of the formation of side product 19.
Scheme 6. Proposed cycloaddition models of endo/exo diastereoselectivity.
Please cite this article in press as: J. He, et al., Intramolecular (4 + 3) cycloadditions of nitrogen-tethered epoxy enosilanes for the synthesis of
heteropolycycles, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.04.051

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J. He et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
Synthetic Chemistry; and the University of Hong Kong. We thank
the University of Hong Kong for a University Postgraduate
Fellowship to JH, a Hung Hing Ying Postgraduate Scholarship to
JPLN, and exploratory work by Dr. Kong Ching Wong.
Appendix A. Supplementary data
Supplementary material related to this article can be
found, in the online version, at doi:https://doi.org/10.1016/j.
cclet.2019.04.051.
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In summary, complex bis-heteroatomic polycyclic adducts were
synthesized from the (4 + 3) cycloadditions of epoxy enolsilanes
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This work was supported by the Research Grants Council
General Research Fund (No. 17301314); the State Key Laboratory of
Please cite this article in press as: J. He, et al., Intramolecular (4 + 3) cycloadditions of nitrogen-tethered epoxy enosilanes for the synthesis of
heteropolycycles, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.04.051