Rhodium(I)-Catalyzed Intermolecular Aza-[4+3] Cycloaddition of Vinyl Aziridines and Dienes: Atom-Economical Synthesis of Enantiomerically Enriched Functionalized Azepines

Article abstract of DOI:10.1002/anie.201609608

A new synthetic application of vinyl aziridines as N-containing three-atom components in a rhodium-catalyzed [4+3] cycloaddition reaction is described. The reaction proceeds well with various silyl dienol ethers and vinyl aziridines, and enables the efficient synthesis of highly functionalized azepines in an enantioselective manner with net inversion of absolute configuration. The salient features of the transformation include the use of readily available substrates, high selectivity, and mild reaction conditions, as well as the versatile functionalization of the products.

Full text of DOI:10.1002/anie.201609608

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International Edition: DOI: 10.1002/anie.201609608
German Edition: DOI: 10.1002/ange.201609608
Asymmetric Synthesis
Rhodium(I)-Catalyzed Intermolecular Aza-[4+3] Cycloaddition of
Vinyl Aziridines and Dienes: Atom-Economical Synthesis of
Enantiomerically Enriched Functionalized Azepines
Chao-Ze Zhu, Jian-Jun Feng,* and Junliang Zhang*
Abstract: A new synthetic application of vinyl aziridines as N-
containing three-atom components in a rhodium-catalyzed
[4+3] cycloaddition reaction is described. The reaction
proceeds well with various silyl dienol ethers and vinyl
aziridines, and enables the efficient synthesis of highly
functionalized azepines in an enantioselective manner with
net inversion of absolute configuration. The salient features of
the transformation include the use of readily available
substrates, high selectivity, and mild reaction conditions, as
well as the versatile functionalization of the products.
Chiral azepines, a class of seven-membered N heterocycles,
are valuable skeletons found in numerous biologically active
natural products and pharmaceuticals (Scheme 1).[1a] For
example, stemoamide is a typical Stemona alkaloid isolated
from Stemona tuberosa Lour., a Chinese folk medicine for
respiratory disorders and also used as an antihelminthic
agent.[1b] Apart from antiaddictive properties, ibogamine
shows potent anticholinesterase activity.[1c] (À)-Securinine
can be used for the treatment of serious diseases, such as
amyotrophic lateral sclerosis (ALS) and poliomyelitis.[1d]
Clinically used (À)-eptazocine is a useful opioid analgesic
for surgical procedures.[1e] Meanwhile, azepine derivatives
also serve as key building blocks in the synthesis of
structurally complex targets, such as iboxyphylline and
glucosepane.[1f,g] Therefore, the development of efficient
methods for the synthesis of azepines is highly attractive.
However, relative to reactions to construct five- and six-
membered N heterocycles, the development of efficient
methodologies for the construction of azepine skeletons is
often much more difficult because of the unfavorable entropic
factors and transannular interactions.[2] Furthermore, the
synthesis of seven-membered N heterocycles in an enantio-
selective manner by catalytic methods is much more chal-
lenging and still rare.[3]
Scheme 1. Representative biologically active azepines. Bn=benzyl,
Cbz=carboxybenzyl.
The [m + n] cycloaddition has been established as a reli-
able and atom-economical method for the synthesis of
heterocycles from simple starting materials.[4–6] [4+3] cyclo-
addition reactions are particularly attractive for their remark-
able efficiency and convergence in the synthesis of azepines,
and diverse three-carbon (3C) and aza-3C dienophiles have
been developed (Scheme 2).[5,6] For example, Shapiro and
Toste[5a] and Chen, Hu, and co-workers[5b] developed elegant
gold-catalyzed [(aza-4C) + 3C] cycloaddition reactions for the
synthesis of azepines by using vinyl gold carbenes as 3C
dienophiles. Allylic phosphonium ylides have also been
shown to act as 3C partners in [4+3] cycloaddition reactions
by Chen and co-workers.[5c] Furthermore, impressive progress
has been made in [4C+(aza-3C)] cycloaddition processes. For
example, Jeffrey and co-workers[5d,e] have carried out seminal
studies on the cycloaddition of transient aza-oxyallylic cations
with dienes. The research groups of Sarpong,[5f] Tang,[5g,h] and
Lee[5i] have independently demonstrated elegant rhodium-
(II)-catalyzed formal [4+3] cycloaddition reactions of alkenyl
rhodium(II) iminocarbene intermediates with dienes, thus
providing efficient access to 2,5-dihydroazepines. Moreover,
azomethine ylides have also been utilized in
[4+(aza-3C)] cycloaddition reactions by the Wang group.[5j]
Although various dienophiles have been discovered, the
[*] C.-Z. Zhu, Dr. J.-J. Feng, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, School of Chemistry and Molecular Engineering
East China Normal University
Shanghai, 200062 (P. R. China)
E-mail: jjfeng@chem.ecnu.edu.cn
jlzhang@chem.ecnu.edu.cn
Prof. Dr. J. Zhang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, CAS
345 Lingling Road, Shanghai 200032 (China)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201609608.
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rhodium intermediate is more difficult than with alkynes. It
may lead to erosion of the ee value of the cycloadduct.[8]
Finally, dienes are good ligands for rhodium complexes and
may therefore deactivate the rhodium catalyst.[10]
In preliminary experiments, we applied the reaction
conditions we previously developed for the [3+2] cyclo-
addition of vinyl aziridines and alkynes to the current reaction
of (R)-1a with dienes 2 possessing different silyl protecting
groups (2a (R4 = Me, Si = TES, triethylsilyl), 2b, 2d) and
observed the formation of the [4+3] cycloadduct 3 in
moderate yield together with a trace amount of g-amino
ketone 4aa with erosion of the ee value. After many attempts,
we finally found that the [4+3] cycloaddition of (R)-1a with
2d proceeded very well in 1,2-dichloroethane (DCE) at 08C
in the presence of [{Rh(NBD)Cl}2]/AgClO4 to give the [4+3]
cycloadduct 3ad in 88% yield (according to NMR spectros-
copy) with 98% ee, with net inversion of the absolute
configuration (see Table S1 in the Supporting Information).
The structure and absolute configuration of the cycloadduct
(S)-3ad was determined unambiguously by X-ray crystallo-
graphic analysis.[11]
Having established optimal reaction conditions, we first
examined the scope of this cycloaddition by variation of the
substitution pattern of the silyl dienol ether (Scheme 3). In
the case of silyl dienol ethers 2b–d, the [4+3] reactivity
increased from TBS to TIPS to TBDPS substitution in terms
of yield. The substituent R4 can be alkyl (substrates 2d–2h),
benzyl (substrate 2i), and aryl (substrates 2j–l). The chirality
of (R)-1a could be efficiently or completely transferred to the
functionalized azepines with 96–98% ee in moderate to high
yields. Notably, the reaction was found to be sensitive to the
electronic effect of the R4 substituent. Substrate 2l with an
electron-withdrawing group (F) at the para position of the
phenyl ring showed higher reactivity than substrate 2k
bearing an electron-donating group. Moreover, diene (S)-2h
containing a stereogenic center gave (S,S)-3ah as a single
diastereomer. The reaction was not limited to 2,3-disubsti-
tuted dienes. The treatment of (R)-1a with the monosubsti-
tuted diene 2m under the standard reaction conditions
furnished the azepine (S)-3am in moderate yield with an
excellent ee value.
Next, the reactions of various substituted vinyl aziridines
with dienes were investigated. The reaction of N-nosyl vinyl
aziridine 1c with 2d gave the [4+3] cycloadduct in higher
yield than that observed with the N-tosyl or N-mesyl vinyl
aziridine (Scheme 3, 3cd versus 3bd versus 3dd). Moderate
yields and high efficiency of chirality transfer were observed
for substrates 1b, 1e, 1 f, and 1g, in which the R2 group was
a H atom or an n-butyl, phenyl, or vinyl group, respectively.
Substrate 1h was also applicable to the [4+3] cycloaddition,
but gave the corresponding cycloadducts with lower ee values
and yield, possibly as a result of the relative facile racemiza-
tion of the starting material under the reaction conditions.[12]
Finally, the reaction is amenable to the gram-scale syn-
thesis of functionalized azepines, as exemplified with sub-
strate (R)-1c (Scheme 4). The functionality present in the
[4+3] cycloadducts provides many opportunities for deriva-
tization. The p-nosyl group was readily removed in the
presence of PhSH/K2CO3. Olefin cross-metathesis converted
Scheme 2. [4+3] cycloaddition for the synthesis of azepines. Bz=ben-
zoyl, EWG=electron-withdrawing group.
discovery of new 3C or aza-3C synthons are still highly
desirable for further enrichment of the structural diversity of
the azepine products. Despite the significant advances made
in this area for the synthesis of achiral or racemic azepines,
there are only few enantioselective examples of these [4+3]
cycloaddition reactions.[3e]
As versatile small rings, vinyl aziridines are commonly
used as the three-atom component in [3+2] cycloaddition
reactions with activated alkenes.[7] Recently, the rhodium-
catalyzed intermolecular [5+2] cycloaddition of vinyl azir-
idines with unactivated alkynes has been developed by our
research group for the synthesis of azepines.[8] Although
a series of achiral azepines can be prepared by the [5+2]
approach, only one reaction afforded a chiral 2,5-dihydroa-
zepine (72% ee). Given the great importance of chiral
azepines, we envisioned that the [4+3] cycloaddition of
optically pure vinyl aziridines with silyl dienol ethers might
serve as a new approach to enantiomerically enriched
azepines through a chirality-transfer strategy via an enyl
(s + p) rhodium intermediate. However, this hypothesis faced
considerable challenges. For example, reactions of vinyl
aziridines with alkenes usually result in [3+2] cycloadducts
or products of ring opening.[7] Chiu and co-workers have
demonstrated the [4C + 3C] cycloaddition of aziridinyl enol-
silanes with cyclic dienes to afford aminoalkylated cyclo-
heptenones.[9a] In contrast, the use of a vinyl aziridine as an
aza-3C dienophile for the synthesis of azepines is still
unknown. The use of alkenes to capture the enyl (s + p)
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(Scheme 1). The disubstituted
double bond could be selectively
hydrogenated to produce the cor-
responding product 7 in 98% yield
without the loss of enantiomeric
purity. The treatment of 7 with
ethyl propiolate and Tf2NH pro-
vided the desired [2+2] cyclo-
adduct
8 in 51% yield with
92% ee.[13a] Notably, 7 was con-
verted into the enantiomerically
pure azocane 9, which has the
core structure of otonecine, by
a sequence of cyclopropanation
followed by ring enlargement.[13b]
To clarify the mechanism, we
examined the reaction of (R)-1a
with the cyclic silyl enol ether 2n
under the standard conditions
[Eq (1)]. The reaction gave 4an in
33% yield together with the [3+2]
cycloadduct 10an in 60% yield and
95% ee with the inversion of con-
figuration.[11] To test whether the
[4+3] cycloadduct arose from rear-
rangement of the [3+2] cyclo-
adduct, we subjected 10an to con-
ditions A at 808C for 12 h. Signifi-
cantly, it was found that 10an was
readily converted into 4an in 65%
yield with 97% ee, whereas the
corresponding [4+3] cycloadduct
was not observed. Different Lewis
acids, such as Cu(SbF6)2, Cu-
(ClO4)2, Sc(OTf)3, FeCl3, and
BF3–Et2O, were tested but also
failed to give the [4+3] cycload-
duct; instead, 4an was obtained as
the major product (see Table S2).
On the basis of the results
above, a plausible mechanism is
proposed in Scheme 5. Thus, both
the olefin and the nitrogen atom in
vinyl aziridine (R)-1 coordinate to
the rhodium catalyst to give com-
plex I, and oxidative addition leads
to the enyl (s + p) rhodium species
II with the retention of configura-
tion.[8,14b] Subsequently, nucleo-
philic attack of the silyl enol ether
Scheme 3. Exploration of the scope of the reaction. Optimal conditions: (R)-1 (0.2 mmol), 2
(1.5 equiv), [{Rh(NBD)Cl}2] (5 mol%), AgClO4 (10 mol%), DCE (2.0 mL), 08C. Yields are for the
isolated product. [a] 2b (Si=TBS), 3ab (55% yield) together with 4aa (22% yield, 87% ee). [b] 2c
(Si=TIPS), 3ac (70% yield) together with 4aa (9% yield, 97% ee). NBD=norbornadiene, Ns=2-
nitrobenzenesulfonyl, TBDPS=tert-butyldiphenylsilyl, TBS=tert-butyldimethylsilyl, TIS=triisopropyl,
Ts =p-toluenesulfonyl.
(S)-3cd into the unsaturated ester (S)-3id in
a highly stereoselective fashion. Moreover, the
silyl group in (S)-3ad could be removed with HF/
pyridine to give the substituted azepan-4-one 6 in
84% yield with d.r. 76:24. This valuable skeleton
is found in many natural products and pharma-
ceuticals, such as iboxyphylline ketone
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valuable natural products and pharmaceuticals
containing chiral azepine skeletons.
Acknowledgements
We are grateful for the funding support of
Shanghai Sailing Program (15YF1403600), the
NSFC (21602062, 21425205), the 973 Program
(2015CB856600), and the Ministry of Education
(IRT12040).
Conflict of interest
The authors declare no conflict of interest.
Keywords: [4+3] cycloaddition · chiral azepines ·
chirality transfer · dienes · vinyl aziridines
Scheme 4. Gram-scale reaction and synthetic transformations. DCM=dichloro-
methane, Py=pyridine, TBAF=tetrabutylammonium fluoride, Tf=trifluoromethane-
sulfonyl.
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Scheme 5. Proposed mechanism.
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the oxonium ion intermediate III with net inversion of the
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net inversion of the absolute configuration, in contrast to
previously reported [3+2] and [5+2] cycloaddition reac-
tions.[7,8] A gram-scale experiment and the versatility of the
[4+3] cycloadducts for further transformations suggest that
this approach will find broad application in the synthesis of
4
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g-amino ketones
4 and [3+2] cycloadducts 10 with high
diastereoselectivity and stereospecificity (see Figure S1 in the
Supporting Information).
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[15] The proposed mechanism is outlined in detail in Figure S2 of the
Supporting Information.
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[7] For reviews on the chemistry of vinyl aziridines, see: a) Azir-
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Manuscript received: October 6, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Synthesis
C.-Z. Zhu, J.-J. Feng,*
J. Zhang*
&&&& — &&&&
Rhodium(I)-Catalyzed Intermolecular
Aza-[4+3] Cycloaddition of Vinyl
Aziridines and Dienes: Atom-Economical
Synthesis of Enantiomerically Enriched
Functionalized Azepines
Strike a happy medium: The title reaction,
in which the vinyl aziridine acts as an aza-
three-atom component, provided highly
functionalized azepines in an enantio-
selective manner with net inversion of
configuration (see scheme; Si is a silyl
protecting group). This strategy features
the use of readily available substrates,
high selectivity, mild reaction conditions,
ease of scale-up, and versatile function-
alization of the products.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!