Modular Access to the Stereoisomers of Fused Bicyclic Azepines: Rhodium-Catalyzed Intramolecular Stereospecific Hetero-[5+2] Cycloaddition of Vinyl Aziridines and Alkenes

Article abstract of DOI:10.1002/anie.201509185

The first rhodium-catalyzed intramolecular hetero-[5+2] cycloaddition reaction of vinyl aziridines and alkenes was realized, wherein both internal and terminal alkenes were applicable. With this method, a variety of unique substituted chiral fused bicyclic azepines, bearing multiple contiguous stereogenic centers, were facilely accessed in a straightforward, high-yielding, and highly stereoselective manner under mild reaction conditions. Notably, the E/Z geometry of the C=C bonds in the vinyl aziridine-alkene substrates impact the cis/trans stereochemistry of the cycloadducts and up to six stereoisomers could be delivered.

Full text of DOI:10.1002/anie.201509185

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International Edition: DOI: 10.1002/anie.201509185
German Edition: DOI: 10.1002/ange.201509185
Heterocycles
Modular Access to the Stereoisomers of Fused Bicyclic Azepines:
Rhodium-Catalyzed Intramolecular Stereospecific Hetero-[5+2]
Cycloaddition of Vinyl Aziridines and Alkenes
Jian-Jun Feng, Tao-Yan Lin, Hai-Hong Wu, and Junliang Zhang*
Abstract: The first rhodium-catalyzed intramolecular hetero-
[5+2] cycloaddition reaction of vinyl aziridines and alkenes
was realized, wherein both internal and terminal alkenes were
applicable. With this method, a variety of unique substituted
chiral fused bicyclic azepines, bearing multiple contiguous
stereogenic centers, were facilely accessed in a straightforward,
high-yielding, and highly stereoselective manner under mild
tially more difficult than those involving alkynes or allenes.[6]
This difficulty arises from the formation of complex mixtures
resulting from the competing and rapid b-hydride elimination
for those substrates bearing internal alkenes. This limitation
to terminal alkenes would preclude the rapid access to the
bicyclo[5.3.0.]decane cores, bearing two or more chiral
centers, in some natural-product families. To overcome this
limitation, the [5+2] cycloaddition of VCPs and allenes has
been developed as an alternative and efficient solution to this
problem (Scheme 1a).[5k–m]
While the systematic study of the [5+2] cycloaddition of
VCPs and 2p-components has been carried out for construc-
tion of fused bicycle[5.3.0.]decane skeletons, the synthesis of
fused azepine derivatives by hetero-[5+2] cycloaddition still
lags behind.[7] The ubiquity of these units in many biologically
=
reaction conditions. Notably, the E/Z geometry of the C C
bonds in the vinyl aziridine-alkene substrates impact the cis/
trans stereochemistry of the cycloadducts and up to six
stereoisomers could be delivered.
M
ethodologies that provide stereodefined, sp3-carbon-rich
scaffolds will underpin future advances in small-molecule
drug design.[1] Among them, the synthesis of seven-membered
carbocycles and heterocycles bearing multiple stereogenic
centers is a topic of continued interest because of the presence
of this skeletal unit in numerous natural products and
pharmaceuticals with diverse biological and medicinal prop-
erties, such as antitumor, antibiotic, and antiinflammatory
activity.[2] Consequently, considerable effort has been devoted
to the development of efficient methods for the synthesis of
these seven-membered rings.[3]
Transition-metal-catalyzed cycloadditions represent pow-
erful tools enabling quick and efficient access to polycyclic
carbo- and heterocycles in an atom-economical fashion. In
particular, using small-ring compounds as cycloaddition
partners brings opportunities for developing novel reactions
which complement or surpass traditional cycloadditons.[4]
Among them, rhodium(I), ruthenium(II), and other transi-
tion-metal catalysts catalyze intramolecular [5+2] cycloaddi-
tion of vinylcyclopropanes (VCPs) and 2p-components, thus
providing a practical way for synthesis of fused bicyclo-
[5.3.0.]decane skeletons.[5] Notably, the [5+2] cycloaddition of
VCPs and alkenes could efficiently increase sp3-carbon
content in the product and thus attract much interest, but it
poses a considerable challenge.[5n,o] An extensive computa-
tional study by Wender, Houk, Yu, and co-workers[6c] showed
that the reductive elimination involving alkenes is substan-
[*] Dr. J.-J. Feng, T.-Y. Lin, Prof. Dr. H.-H. Wu, 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: jlzhang@chem.ecnu.edu.cn
Homepage: http://faculty.ecnu.edu.cn/s/1811/main.jspy
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509185.
Scheme 1. [5+2] cycloadditions and hetero-[5+2] cycloadditions.
Ts =4-toluenesulfonyl.
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Table 1: Exploration of substrate scope.[d]
active alkaloids, such as tetrapetalone A, fawcettimine, ste-
moamide, and cephalotaxine, make the development of new
stereoselective strategies to access stereoisomers of fused
bicyclic azepines in one step, from readily available acyclic
precursors, highly desirable (Figure 1).[2c,8] Inspired by the
Figure 1. Natural products featuring ring-fused azepines.
pioneering works on the rhodium-catalyzed hetero-[5+2]
cycloaddition of cyclopropyl imines with electron-deficient
alkynes, developed by the research group of Wender,[7a] we
recently developed a rhodium(I)-catalyzed intramolecular
hetero-[5+2] cycloaddition of optically pure vinyl aziridine-
alkyne substrates for the synthesis of enantioenriched fused
2,5-dihydroazepines through
a chirality-transfer strategy
(Scheme 1b),[9a] which is complementary to the [4+3]
method reported by the groups of Sarpong and Tang.[10] For
increasing the sp3-carbon content in the cycloadduct, one
straightforward but challenging way is to replace of the
alkynes by the alkenes in this reaction, thus leading to
previously unexplored issues of mechanism [reductive elim-
3
3
À
À
[a] Average yield of products isolated form the reactions of (+)-1 and its
enantiomer. For all substrates in Table 1 the E-configured alkene was
used. [b] Reaction conditions A: [Rh(h6-C10H8)(COD)]SbF6 (5 mol%),
DCE (0.067 M), 30 oC. [c] Reaction conditions B: [{Rh(NBD)Cl}2]/AgSbF6
(5 mol%), DCE (0.067 M), 80 oC. [d] Reaction conditions C: [Rh(IPr)-
(COD)Cl]/AgSbF6 (5 mol%), DCE (0.067 M), 80 oC. [e] 10 mol% catalyst.
ination of an C(sp ) Rh N(sp ) intermediate versus com-
petitive b-hydride elimination] and stereochemistry. Herein,
we report the first example of rhodium(I)-catalyzed hetero-
[5+2] cycloadditions between vinyl aziridines and alkenes
(Scheme 1c). Several points are noteworthy: 1) the reaction
proceeds under mild reaction conditions with a broad sub-
strate scope; 2) the transformation is very practical and
completely regio- and stereoselective; 3) it provides an atom-
economic and stereospecific protocol to valuable chiral fused
bicyclic azepines bearing two or three contiguous stereogenic
centers through a chirality-transfer strategy; 4) theoretically,
a compound bearing three chiral centers will afford eight
stereoisomers, thus, the development of methodology which
provides most of the stereoisomers is highly desirable but
poses considerable challenges. We found that a slight struc-
Under the optimal reaction conditions, a series of vinyl
aziridine-alkenes (1) were prepared and examined (Table 1).
The results indicate that the present transformation is tolerant
of tethers incorporating sulfonamide (1a,b), geminal diester
(1c), and ether (1d) functionalities under reaction condi-
tions A, thus delivering the corresponding cycloadducts as
single cis-fused diastereomers. The structure and absolute
configuration of the product (S,S)-2a were established by X-
ray crystallographic analysis.[12] Variation of the substitution
patterns on the aziridine moiety, and using the reaction
conditions A, resulted in the undesired decomposition of the
substrates 1e–h and 1k. Gratifyingly, treatment of these
substrates with 5 mol% [{Rh(NBD)Cl}2]/AgSbF6 in DCE at
808C delivered the corresponding products in moderate to
good yields (reaction conditions B). Importantly, the sub-
strate 1h, having a trisubstituted alkene moiety, reacted well
under reaction conditions B without any detectable amount
of olefin isomerization. In contrast, 1g, lacking methyl
substitution of the alkene group, gave 2g in 34% yield
(NMR). The use of [Rh(IPr)(COD)Cl]/AgSbF6 as the catalyst
significantly improved the yield to 60%. The substrates 1i and
1j, bearing two methyl groups at the allylic position, were also
successfully converted into the desired cycloadducts 2i and
2j, respectively. Notably, both terminal and internal alkenes
=
tural variation of the E/Z geometry of the C C bonds and the
stereochemistry of the aziridine moiety in the vinyl aziridine-
alkene substrates could yield up to six stereoisomers of the
cycloadducts.
The vinyl aziridine-alkene substrate (S,6E)-1a can be
easily prepared in 99% ee from commercially available d-
serine methyl ester hydrochloride.[11] After many attempts,
gratifyingly, with the use of [Rh(IPr)(COD)Cl]/AgSbF6
(COD = 1,5-cyclooctadiene), the cycloaddition reaction pro-
vided the desired product in 90% yield (NMR) and 99% ee
in DCE at 808C. [Rh(h6-C10H8)(COD)]+SbF6 and [Rh-
À
(NBD)Cl]2/AgSbF6 (NBD = norbornadiene) were more effi-
cient for the reaction, and can catalyze the reaction at 308C.
Different silver salts, such as AgOTf and C3F7CO2Ag, were
investigated but failed to improve the process (see Table S1,
in the Supporting Information).
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were compatible and afforded the corresponding substituted
fused 2,3,6,7-tetrahydroazepine scaffolds (2l–p). Interestingly
but surprisingly, the cycloadducts from vinyl aziridine-inter-
nal alkenes prefers a trans ring-fusion rather than a cis ring-
fusion from the terminal alkenes (2l versus 2a). Unfortu-
nately, the substrate 1o, bearing a methyl group at the alkene
terminus, delivered the corresponding 2o in only 15% yield,
along with some byproducts from the competitive b-hydride
elimination.[13] Gratifyingly, the compound 1p, bearing an
alkenyl group, which serves as a masked alkyl group at the
alkene terminus, reacted smoothly to afford the product 2p.
Moreover, complete chirality transfer could be achieved for
substrates (+)-1 and (À)-1, thus indicating the present
transformation is highly stereospecific.
hetero-[5+2] cycloaddition was investigated. Interestingly,
the third diastereomer (S,S,R)-2l, and (R)-3l together with
(S,R,R)-2l were obtained when (S,1Z,6E)-1l was employed as
the starting material. Whereas (R,R,S)-2l was observed when
we subjected (S,1Z,6Z)-1l to the same reaction conditions.
The structures of (R,S,R)-2l, (R,S,S)-2l, and (S,S,R)-2l were
confirmed by single-crystal X-ray diffraction.[12]
Based on the above chirality-transfer experiment, a ration-
alization is outlined in Scheme 3 to address this stereocontrol
issue. As exemplified in Scheme 3a for (S,6E)-1, having
To further explore the scope and mechanistic details of
this hetero-[5+2] cycloaddition, we extensively studied the
=
influence of the E/Z geometry of the C C bonds and the
stereochemistry of the aziridine moiety on the stereochem-
istry of the cycloadducts (Scheme 2). Interestingly, the
Scheme 3. Proposed mechanism.
E geometry in the vinyl aziridine moiety. Firstly, the rhodium
catalyst p-facial selectivity coordination to ene-ene moieties
of the enantioenriched 1 would give either the intermediate
IA or IB, which would in turn undergo oxidative cyclo-
metallation of the 1,6-diene moiety to afford the diastereo-
meric metallacyclo-pentenes IIA and IIB, respectively. After
Scheme 2. Gram-scale reaction and access to the six stereoisomers of
the fused azepine derivatives.
À À À
rotating around the Ha C C Hb bond to align the carbon–
À
rhodium and aziridine C N bonds for cleavage, and to
reactions of the substrates (S,6E)-1a and (S,6Z)1a are
amenable to a gram-scale synthesis of the corresponding
products (R,R)-2a and (S,S)-2a, featuring a cis ring-fusion but
with opposite configurations. However, the stereoselectivity
was shifted toward the formation of a trans-ring-fusion
product for substrate (S,1E,6E)-1l. More surprisingly,
position the remaining group in the geometry required for the
formation of the cis-alkene, the b-nitrogen elimination of the
intermediates IIIA and IIIB take place, thus leading to IVA
and IVB, respectively. Finally, reductive eliminations of the
3
3
À
À
C(sp ) Rh N(sp ) bond from these species produce the cis
ring-fused and trans ring-fused products 2, and regenerate the
rhodium catalyst. When R1 = Ph and R2 = H, the steric
interaction between the R1 and the aziridine moiety in IIIA
likely disfavors the formation of the intermediate that leads to
IVA. Thus the reaction gave the trans ring-fused products
(R,S,R)-2l by path b. In contrast, when R1 = R2 = H [(S,6E)-
=
a slight structural variation of the E/Z geometry of the C C
bonds in the vinyl aziridine moiety [(S,1E,6Z)-1l] allowed
switching of the reaction to yield (R,S,S)-2l as a single
diastereomer with cis-ring-fusion. Subsequently, the E/Z ge-
ometry of the double bond in the two-carbon synthons of the
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1a] or R1 = H, R2 = Ph [(S,1Z,6E)-1l], the formation of IIIA
is intrinsically favored and leads to the cis ring-fused product
2 by path a and (R)-3l through the competitive b-hydride
elimination pathway. The observed highly efficient chirality
transfer is thus a consequence of the reversibility of the initial
mechanistic steps and the influence of the substituent on
a later step, putatively involving irreversible cleavage of the
aziridine. The stereocontrol issue with respect to substrate the
(S,6Z)-1, bearing Z geometry in the vinyl aziridine moiety, is
also in agreement with the model (Scheme 3b).[14]
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In summary, we have developed a general approach to sp3-
carbon-rich fused tetrahydroazepine scaffolds by a rhodium-
catalyed intramolecular stereospecific hetero-[5+2] cyclo-
addition of vinyl aziridines and alkenes under mild reaction
conditions. This method delivers valuable fused azepines
bearing multiple contiguous stereogenic centers with broad
substrate scope and high enantioselectivity (up to 99% ee) by
a chirality-transfer strategy. Moreover, our studies highlight
that a slight structural variation of the E/Z geometry of the
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C. O. Husfeld, E. Langkopf, J. A. Love, J. Am. Chem. Soc. 1999,
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=
C C bonds and the stereochemistry of the aziridine moiety in
the vinyl aziridine-alkene substrates can enable reactions to
afford up to six stereoisomers of the cycloadducts. Further
mechanism and synthetic application of this transformation
are underway.
Acknowledgements
We grateful to the funding support of Science and Technology
Commission of Shanghai Municipality (15YF1403600), NSFC
(21373088, 21425205).
Keywords: chirality · cycloaddition · heterocycles · rhodium ·
stereoselectivity
How to cite: Angew. Chem. Int. Ed. 2015, 54, 15854–15858
Angew. Chem. 2015, 127, 16080–16084
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[14] An alternative mechanism was suggested by a reviewer, and it
involves the formation of six-membered metallacycle derived
from the oxidative addition of rhodium catalyst with vinyl
aziridine moiety (see Figure S2 in the Supporting Information).
Received: October 2, 2015
Published online: November 11, 2015
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