Intermolecular Regio- and Stereoselective Hetero-[5+2] Cycloaddition of Oxidopyrylium Ylides and Cyclic Imines

Article abstract of DOI:10.1002/anie.201811896

We have developed the first intermolecular hetero-[5+2] cycloaddition reaction between oxidopyrylium ylides and cyclic imines with excellent control of regio- and stereoselectivity. Surprisingly, divergent stereochemistry was observed depending on the substitution pattern of the oxidopyrylium ylide. This new reaction provides quick access to highly substituted nitrogen-containing seven-membered rings—azepanes. Notably, a broad range of oxidopyrylium ylides and cyclic imines participate in this novel hetero-[5+2] cycloaddition reaction and the cycloadducts can be readily transformed into the core skeletons of bioactive natural products. DFT calculations revealed that the cycloaddition proceeds through a stepwise pathway and the imine nitrogen atom serves as the nucleophile to initiate the cycloaddition.

Full text of DOI:10.1002/anie.201811896

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Accepted Article
Title: Intermolecular Regio- and Stereoselective Hetero-[5+2]
Cycloaddition between Oxidopyrylium Ylide and Cyclic Imine:
Facile Access to Highly Substituted Azepanes
Authors: Changgui Zhao, Daniel A. Glazier, Daoshan Yang, Dan Yin,
Ilia A. Guzei, Michael M Aristov, Peng Liu, and Weiping Tang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811896
Angew. Chem. 10.1002/ange.201811896
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Intermolecular Regio- and Stereoselective Hetero-[5+2]
Cycloaddition of Oxidopyrylium Ylides and Cyclic Imines
Changgui Zhao, Daniel A. Glazier, Daoshan Yang, Dan Yin, IIia A. Guzei, Michael M. Aristov, Peng
Liu* and Weiping Tang*
Abstract: We developed the first intermolecular hetero-[5+2]
cycloaddition reaction between oxidopyrylium ylide and cyclic imine
with excellent control of regio- and stereoselectivity. Surprisingly,
divergent stereochemistry was observed depending on the
substitution pattern of the oxidopyrylium ylide. This new reaction
provides quick access to highly substituted nitrogen-containing
seven-membered rings – azepanes. Notably, a broad range of
oxidopyrylium ylides and cyclic imines participated in this novel
hetero-[5+2] cycloaddition reaction and the cycloadducts can be
readily transformed into core skeletons of bioactive natural products.
DFT calculations reveals that the cycloaddition proceeds through a
stepwise pathway and the imine nitrogen atom serves as the
nucleophile to initiate the cycloaddition.
version of the oxidopyrylium-based [5+2] cycloaddition is much
less studied and the substituent effect of oxidopyrylium ylide on
endo/exo selectivity remained underexplored.[5-7] Furthermore,
despite the importance of the oxidopyrylium-based [5+2]
cycloadditions, the 2π partners have been limited to alkenes,
dienamine, trienamine and alkynes to date. To the best of our
knowledge, no hetero-[5+2] cycloaddition of oxidopyrylium ylide
has ever been reported.
As part of our continuous efforts on developing of novel [5+2]
cycloaddition reactions,[11] we became interested in the synthesis
of highly substituted nitrogen-containing seven-membered
heterocycles - azepanes by hetero-[5+2] cycloadditions as shown
in Scheme 1A. Azepanes are presented in numerous natural
products such as rubenine,[12] cadambine[13] and banistenoside[14]
(
Scheme 1B), which possess complex penta- and even hexa-
Cycloaddition reaction is one of the most efficient and powerful
ways to build molecular complexity. Although various
cycloaddition reactions have been developed for the synthesis of
complex four-, five- and six-membered rings with excellent control
of regio- and stereoselectivity, much less methods are available
for the formation of highly substituted seven-membered rings.[
Since the first report by Hendrickson in 1980,[4] oxidopyrylium
ylide-based [5+2] cycloaddition[5] has emerged as a powerful
transformation for the construction of seven-membered
carbocycles.[2,6,7] Most previous studies focused on intramolecular
oxidopyrylium-alkene cycloaddition with the alkene 2π
components tethered to C2 or C6 position, representing the type
substituted azepane cores. The feasibility, regio-, and
stereoselectivty of the proposed hetero-[5+2] cycloaddition are
entirely unknown. We herein describe the first hetero-[5+2]
cycloaddition of oxidopyrylium ylide with cyclic imines in excellent
regio- and stereoselectivity. DFT calculations were also carried
out to further understand the reaction mechanism.
1-3]
Scheme 1. A) Hetero-[5+2] cycloaddition of oxidopyrylium ylide with imine; B)
Representative highly substituted azepane-containing natural products.
Ⅰ
oxidopyrylium-alkene cycloaddition.[6] In 2015, Li’s group
demonstrated that type Ⅱ [5+2] cycloaddition was feasible by
tethering the alkene to the C5 position of oxidopyrylium ylide,
which leads to various highly functionalized bridged seven-
membered carbocycles.[8] This reaction was then applied to the
construction of the carbon core of eurifoloid A[9] and the total
synthesis of isocyclocitrinol.[10] In contrast, the intermolecular
[
a]
Dr. C. Zhao, Prof. Dr. D. Yang, Prof. Dr. W. Tang
School of Pharmacy
University of Wisconsin-Madison
Madison, WI 53705 (USA)
E-mail: weiping.tang@wisc.edu
D. A. Glazier, D. Yin, Dr. I. A. Guzei, M. M. Aristov, Prof. Dr. W.
Tang
Department of Chemistry, University of Wisconsin-Madison
Madison, WI 53706 (USA)
Prof. Dr. D. Yang
State Key Laboratory Base of Eco-Chemical Engineering, College of
Chemistry and Molecular Engineering, Qingdao University of
Science and Technology
Qingdao, 266042, China
Prof. Dr. P. Liu
Department of Chemistry, University of Pittsburgh
Pittsburgh, PA 15260 (USA)
E-mail: pengliu@pitt.edu
We first investigated different types of acyclic and cyclic
imines for the hetero-[5+2] cycloaddition with oxidopyrylium ylide
derived from acetoxypyranone 2a in the presence of DBU.[15] We
found that readily available 3,4-dihydroisoquinoline 1a afforded
the desired cycloadduct 3aa along with the dimer of 2a as the
major byproduct (Table 1, entry 1). Slow addition of 2a minimized
the dimerization and resulted in an improvement of the yield (entry
[
b]
c]
[
2). The influence of several solvents on the cycloaddition was also
investigated. We observed that the use of polar solvent such as
acetonitrile led to a decrease in the yield, other solvents did not
improve the yield (entries 3-6). Based on these results,
dichloromethane was chosen as the optimal solvent.
Subsequently, a range of bases including pyridine, DBN, and
triethyl amine were tested for the generation of the oxidopyrylium
[d]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate)
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ylide (entries 7-10). Gratifyingly, we found that DBN afforded the
desired cycloadduct in 78% isolated yield (entry 8). In all cases,
3
aa was isolated as a single isomer.[16]
Table 1. Optimization of the experimental conditions.
[
a] Reaction conditions: under argon atmosphere, 1a (0.2 mmol), 2a (0.4 mmol),
base (3 equiv), solvent (2 mL), at room temperature for 8 h, endo:exo > 20:1
unless noted otherwise. [b] Yield of isolated products. [c] 2a in CH Cl (1 mL)
was added over 4 h. DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene, DBN = 1,5-
Diazabicyclo[4.3.0]non-5-ene, DCE 1,2-dichloroethane, THF
tetrahydrofuran, n.r. = no reaction.
2
2
[
a] Reaction conditions: under argon atmosphere, 1 (0.2 mmol), 2a (0.4 mmol),
2 2
base (3 equiv), CH Cl (2 mL), at room temperature for 8 h, endo:exo > 20:1
unless noted otherwise. [b] Yield of isolated products. [c] 2a in CH Cl (1 mL)
2 2
was added over 4 h. [d] Isolated ratios.
=
=
Having the optimized conditions in hand, we next examined
the scope of 3,4-dihydroisoquinoline by varying the substitution
patterns. As shown in Table 2, the hetero-[5+2] cycloaddition was
found to be applicable to diverse dihydroisoquinolines. A wide
range of substituents can be tolerated on various positions. The
electronic nature and positions of the substituents on the 3,4-
dihydroisoquinoline had an obviously effect on the effectiveness
of the cycloaddition. Electron-donating groups on the aryl ring
generally afforded higher yields of the cycloaddition products. A
To further examine the scope of the imines, we replaced the
phenyl moiety in dihydroisoquinoline by other heteroaryl systems
such as substituted indoles and thiophene (Table 4).
Acetoxypyranones 2a, 2k, and 2m reacted with dihydro-β-
carboline 1p-r to give the corresponding cycloadducts,[16] which
are the core scaffold in natural products shown in Scheme 1B.
To explore the potential utility of this novel hetero-[5+2]
cycloaddition, we further elaborated the functional groups in 3pk
and 3aa as shown in Scheme 2. The azepane core skeleton of
rubenine and cadambine could be obtained through Luche
reduction of α,β-unsaturated ketones and subsequent
hydrogenation of the isolated alkene followed by reductive
Br-group at the C8 position lowered the diastereoselectivity
16]
(
3ia).[ A nitro group on the aryl ring completely shut down the
reaction (3ka). Interestingly, a gem-dimethyl group at the benzylic
position significantly facilitated the cycloaddition (3la).
spirocycle (3ma) is not as effective as dimethyl group in 3la.
A
[17]
cleavage of the N,O-acetal and toluenesulfonyl group with LAH.
Treatment of allylic alcohol 4 with OsO
4
in the presence of TsOH
To further demonstrate the generality of the hetero-[5+2]
cycloaddition, we next set out to exploit the scope of
acetoxypyranones (Table 3). It was found that substituents at
different positions of pyranone were all well tolerated. To our great
surprise, substituents at different position of pyranone provided
completely opposite distereoselectivity. As shown in Table 3,
pyranones with various 2-alkyl substituents gave the
corresponding cycloadducts 3ab–3ad in good yields and with
endo selectivity. Similarly, 2,4- and 2,5-disubstituted pyranones
also gave endo stereoisomer as major product in excellent yields
afforded the desired triol 6 as a single diastereoisomer,[ which
represents the core of banistenoside and related natural
products.[ Furthermore, the cycloaddition product 3aa could
also undergo diastereoselective conjugate addition with a sulfur
nucleophile to yield 7 as a single isomer.
16]
18]
Attempts for the asymmetric hetero-[5+2] cycloaddition with
known chiral catalysts were not successful.[15] However, we were
able to prepare the enantiomerically enriched cyclic imine 1t (89%
ee), which gave the expected exo stereoisomer 3tm (89% ee) as
the major product with excellent control of stereoselectivity. We
did not observe any loss of stereochemical integrity under the
hetero-[5+2] cycloaddition reaction conditions.
(
e.g. 3ae-3aj).[16] On the other hand, substrates lacking the 2-alkyl
substituent favored exo selectivity. In all cases, the [5+2]
cycloaddition proceeded satisfactorily to afford the corresponding
cycloadducts in good to excellent yields with high
diastereoselectivity (3ak-3ao).[16] Furthermore, incorporation of
substituents at the 4- and 5-position had little impact on the
formation of the corresponding products (e.g. 3ap). We also found
that an additional substituent on the 6-position could not be
tolerated.[15]
There are three possible mechanisms for this hetereo-[5+2]
cycloaddition: a) a concerted cycloaddition process (Scheme 1A,
I); b) nucleophilic addition of oxidopyrylium ylide to the imine
carbon followed by ring closure (Scheme 1A, II); and c)
nucleophilic addition of the imine nitrogen to oxidopyrylium
followed by ring closure (Scheme 1A, III). Alkene/oxidopyrylium
Table 2. Scope of dihydroisoquinoline.
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COMMUNICATION
Table 3. Scope of acetoxypyranone.
opposite stereochemistry in >20:1 dr. The free energy profiles of
the reaction of 1a and oxidopyrylium 8m to form 3am are shown
in Scheme 3A. The free energy profiles for the formation of 3aa
are included in the Supporting Information.
Scheme 2. Cycloaddition product diversification and preparation of
enantiomerically enriched cycloadduct.
[
a] Reaction conditions: under argon atmosphere, 1a (0.2 mmol), 2 (0.4 mmol),
base (0.6 mmol), CH Cl (2 mL), at room temperature for 8 h, endo:exo or
exo:endo > 20:1 unless noted otherwise. [b] Yield of isolated products. [c] 2a in
CH Cl (1 mL) was added over 4 h. [d] Isolated ratios. [e] 3.0 eq of 2k was
2
2
, -78 oC; b) Pd/C, H
O; e) PhSH, Et N,
Reagents and coditions: a) CeCl
EtOAc; c) LiAlH , AlCl , THF; d) OsO
CH Cl ; f) DBN, CH Cl
3
, NaBH
4
, MeOH/CH
2
Cl
2
2
,
2
2
4
3
4
, TsOH, acetone/H
2
3
added. [f] 50% probability ellipsoids.
2
2
2
2
.
Table 4. Scope of heterocyclic imines.
Two concerted transition states TS1-exo and TS1-endo were
located, leading to the exo and endo isomers of the
experimentally unobserved isomer 9am. Both TS1-exo and TS1-
endo are highly asynchronous, with a much longer forming
C(imine)−C2 bond (3.16 and 2.40 Å, respectively) than the
forming N(imine)−C6 bond (1.90 and 1.97 Å). This is consistent
with TS structures of inverse-electron-demand hetero-Diels-Alder
reactions with imines.[ The stepwise transition state (TS2) that
forms the N−C6 bond first has a similar barrier compared to that
of TS1-exo. This stepwise transition state leads to a zwitterionic
intermediate Int-1, which then undergoes C(imine)−C2 bond
formation via TS3 to form 9am-endo.[ Concerted transition
states leading to the experimentally observed isomer 3am cannot
be located. Instead, we located a stepwise transition state TS4 in
which the imine N lone pair attacks C2 of 8m to form zwitterionic
intermediate Int-2. Int-2 is also much more stable than Int-1 due
to the more effective resonance delocalization of the enolate
negative charge in the zwitterionic intermediate Int-2. This agrees
with the high regioselectivity observed for the formation of 3am.
From Int-2, C−C bond formation transition states TS5-exo and
TS5-endo lead to the exo and endo cycloadducts 3am and 3am-
endo, respectively. The steric repulsions between the
oxidopyrylium ring and the imine destabilize the endo transition
state TS5-endo. The relatively large free energy difference
between TS5-exo and TS5-endo (∆∆G‡ = 2.5 kcal mol ) is
consistent with the high d.r. (>20:1) that favors the less sterically
encumbered exo products. The reaction with the C2-substituted
oxidopyrylium 8a to form 3aa also occurs via the stepwise
mechanism. In the stereoselectivity-determining C−C bond
formation step, the exo-selective transition state TS6-exo is
destabilized by gauche repulsions between the C2-methyl
20]
21]
[
a] Reaction conditions: under argon atmosphere, 1 (0.2 mmol), base (3 equiv),
solvent (2 mL), 2 (0.4 mmol) in CH Cl (1 mL) was added over 4 h, then room
temperature for 8 h, exo:endo >20:1 unless noted otherwise. [b] 3.0 equiv of 2k
was added. [c] Isolated ratios. [d] 50% probability ellipsoids. [e] RT for 48 h.
2
2
[
5+2] cycloadditions are known to proceed via concerted
mechanisms similar to Scheme 1A, I.[6b],[19] However, the high
-1
regioselectivity and the substituent-dependent diastereo-
selectivity suggests that a stepwise mechanism in Scheme 1A, II
or III may be more likely for the hetereo-[5+2] cycloaddition. This
mechanistic ambiguity prompted us to perform density functional
theory (DFT) calculations to explore the reaction mechanisms and
the origin of regio- and stereoselectivity. We chose to investigate
the reactions to form 3aa and 3am as they gave completely
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substituent and the dihydroisoquinoline methylene group
0840494). Calculations were performed at the University of
(
distance of 2.19 Å, see Scheme 3E). These steric effects make
Wisconsin – Madison High Performance Computing facility.
-1
TS6-endo more stable than TS6-exo by 1.2 kcal mol , leading to
the reversal of the stereoselectivity to form the endo product.
Keywords: oxidoprylium ylide • [5+2] cycloaddition • imines •
heterocycles • azepanes
[
1]
For selected reviews, see: a) L. Ghosez, in: Stereocontrolled Organic
Synthesis, (Ed.: B. M. Trost), Blackwell Science, Oxford, 1994, pp 193–
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Organic Syntheses, Wiley-VCH, Hoboken, 2014.
[
[
2]
3]
For selected reviews on [5+2] cycloadditions, see: a) H. Pellissier, Adv.
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2018, 360, 1551.
For selected examples of hetero-[5
+
2] cycloadditions involving
vinylcyclopropanes, vinyl epoxides, and vinylaziridines, see: a) E. L.
Stogryn, S. J. Brois, J. Am. Chem. Soc. 1967, 89, 605; b) P. A. Wender,
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33‚ 7304.
1
[
[
4]
5]
J. B. Hendrickson, J. S. Farina, J. Org. Chem. 1980, 45, 1261.
For reviews on the oxidopyrylium ylide [5 + 2] cycloadditions, see: a) V.
Singh, U.M. Krishna, Vikrant, G. K. Trivedi, Tetrahedron 2008, 64, 3405;
b) L. P. Bejcek, R. P. Murelli, Tetrahedron 2018, 74, 2501.
[
6]
For selected recent examples of acetoxypyranone-based oxidopyrylium
ylide [5 + 2] cycloadditions with alkenes and alkynes, see: a) N. Z. Burns,
M. R. Witten, E. N. Jacobsen, J. Am. Chem. Soc. 2011, 133, 14578; b)
G. Mei, H. Yuan, Y. Gu, W. Chen, L. W. Chung, C.-C. Li, Angew. Chem.
Int. Ed. 2014, 53, 11051; c) J. A. Simanis, C. M. Law, E. L. Woodal, C.
G. Hamaker, J. R. Goodell, T. A. Mitchell, Chem. Commun. 2014, 50,
9
130; d) M. R. W. E. N. Jacobsen, Angew. Chem. Int. Ed. 2014, 53, 5912;
Scheme 3. Density functional theory (DFT) calculations. DFT calculations were
performed at the M06-2X/6-311++G(d,p)/SMD(dichloromethane) level of theory.
f) A. Orue, U. Uria, E. Reyes, L. Carrillo, J. L. Vicario, Angew. Chem. Int.
Ed. 2015, 54, 3043; e) H. Suga, T. Iwai, M. Shimizu, K. Takahashi, Y.
Toda, Chem. Commun. 2018, 54, 1107.
In summary, the first hetero-[5+2] cycloaddition between
oxidopyrylium ylide and cyclic imine was developed, leading to
highly substituted azepane scaffolds with excellent regio- and
diastereoselectivity confirmed by X-ray crystallographic
analysis.[22] These cycloadducts could be readily transformed into
core skeletons of natural products. DFT calculations reveals that
this hetero-[5+2] cycloaddition proceeds through a zwitterionic
stepwise mechanism and rationalizes the experimentally
observed high regionselectivity and substituent-dependent
stereoselectivity.
[
7]
For selected recent examples on total syntheses of natural products, see:
a) K. C. Nicolaou, Q. Kang, S. Y. Ng, D. Y.-K. Chen, J. Am. Chem. Soc.
2010, 132, 8219. b) M. Zhang, N. Liu, W. Tang, J. Am. Chem. Soc. 2013,
35, 12434; c) B. Chen, X. Liu, Y. J. Hu, D. M. Zhang, L. J. Deng, J. Y. Lu,
L. Min, W. C. Ye, C.- C. Li, Chem. Sci. 2017, 8, 4961.
[8]
G. Mei, X. Liu, C. Qiao, W. Chen, C.-C. Li, Angew. Chem. Int. Ed. 2015,
54, 1754.
[
[
9]
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10] J. Liu, J. Wu, J.-H. Fan, X. Yan, X.; G. Mei, C.-C. Li, J. Am. Chem.
Soc. 2018, 140, 5365.
[
11] For a review on our Rh-catalyzed [5+2] cycloadditions, see: a) C. M.
Schienebeck, X. Li, X.-Z. Shu, W. Tang, Pure Appl. Chem. 2014, 86, 409.
For selected examples of our Rh-catalyzed [5+2] cycloadditions, see: b)
X.-Z. Shu, S. Huang, D. Shu, I. A. Guzei, W. Tang, Angew. Chem. Int.
Ed. 2011, 50, 8153; c) X.-Z. Shu, X. Li, D. Shu, S. Huang, C. M.
Schienebeck, X. Zhou, P. J. Robichaux, W. Tang, J. Am. Chem. Soc.
Acknowledgements
Support for this research was provided by the University of
Wisconsin - Madison Office of the Vice Chancellor for Research
and Graduate Education with funding from the Wisconsin Alumni
Research Foundation, and the University of Pittsburgh Mascaro
Center for Sustainable Innovation. Part of the support for this
project was also provided by NSF (CHE-1464754 and CHE-
2
012, 134, 5211; d) X. Xu, P. Liu, X.-Z. Shu, W. Tang, K. N. Houk, J. Am.
Chem. Soc. 2013, 135, 9271; e) X.-Z. Shu, C. M. Schienebeck, W. Song,
I. A. Guzei, W. Tang, Angew. Chem. Int. Ed. 2013, 52, 13601; f) X.-z.
Shu, C. M. Schienebeck, X. Li, X. Zhou, W. Song, L. Chen, I. A. Guzei,
W. Tang, Org. Lett. 2015, 17, 5128.
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COMMUNICATION
[
[
12] R. Brown, A. Charalmbides, J. C. S. Chem. Comm. 1973, 765.
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[20] M. A. McCarrick, Y.-D. Wu, K. N. Houk. J. Am. Chem. Soc., 1992, 114,
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[21] TS3 leads to 9am-endo, but we couldn't find a TS that leads to 9am from
int-1.
[
[
15] See Supporting Information for details
[22] The detailed supplementary crystallographic data for CCDC1868464,
CCDC1868465, CCDC1868466, CCDC1868467, CCDC1868468, and
CCDC1868469 are included in the Supporting Information. They can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
16] The relative configurations were determined by NOE experiment or X-
ray crystallographic analysis (see Supporting Information for details).
17] Y. Yoshimura, J. Inoue, N. Yamazaki, S. Aoyagi, C. Kibayashi,
Tetrahedron Lett. 2006, 47, 3489.
[
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COMMUNICATION
COMMUNICATION
C. Zhao, D. A. Glazier, D. Yang, D. Yin,
I. A. Guzei, M. M. Aristov, P. Liu,* W.
Tang.*
Page – Page
Intermolecular Regio- and
Stereoselective Hetero-[5+2]
Cycloaddition of Oxidopyrylium
Ylides and Cyclic Imines
Text for Table of Content
The first hetero-[5+2] cycloaddition of oxidopyrylium ylide and cyclic imine has been realized. It provides an efficient way to access
highly substituted azepane scaffolds. DFT calculations indicates that a stepwise mechanism is favored over a concerted one.
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