Templated Assembly of Chiral Medium-Sized Cyclic Ethers via 8-endo-trig Nucleophilic Cyclization of Cyclopropenes

Article abstract of DOI:10.1021/acs.orglett.6b03068

An efficient approach toward enantioenriched eight-membered heterocycles via the intramolecular formal substitution of bromocyclopropanes with oxygen-based nucleophiles has been developed. The reaction proceeds via a reactive cyclopropene intermediate, wh

Full text of DOI:10.1021/acs.orglett.6b03068

Letter
pubs.acs.org/OrgLett
Templated Assembly of Chiral Medium-Sized Cyclic Ethers via
8‑endo-trig Nucleophilic Cyclization of Cyclopropenes
Pavel Ryabchuk,†,‡ Jonathon P. Matheny,† Marina Rubina,† and Michael Rubin*,†,§
†Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United States
‡Leibniz-Institut fur Katalyse e.V. an der Universitat Rostock, Albert-Einstein Straße 29a, Rostock 18059, Germany
̈
̈
§Department of Chemistry, North Caucasus Federal University, 1a Pushkin St., Stavropol 355009, Russian Federation
S
* Supporting Information
ABSTRACT: An efficient approach toward enantioenriched eight-membered heterocycles via the intramolecular formal
substitution of bromocyclopropanes with oxygen-based nucleophiles has been developed. The reaction proceeds via a reactive
cyclopropene intermediate, which undergoes a rapid 8-endo-trig cyclization affording cis-fused [6.1.0] bicyclic products
exclusively. The quaternary chiral center in the cyclopropene governs the configuration of the other two stereocenters in the final
product.
he occurrence of medium-sized heterocycles in nature1
Scheme 1. Different Modes of Cyclizations Involving
Nucleophilic Additions of Alkoxides to Cyclopropenes
2
Tand their privileged position in drug discovery research
justify the unceasing interest in development of efficient
synthetic routes for their assembly. Ring closures to form
medium-sized rings can be achieved by employing various
transition-metal-catalyzed3 and free radical4 methods, yet direct
nucleophilic cyclizations remain underexplored. Synthetic
approaches to 7−12-membered lactones involving intra-
molecular nucleophilic attack by an alkoxide on an activated
carbonyl group are well documented.5 However, analogous
processes employing a less reactive alkene double bond are
rare,6 particularly, the thermodynamically challenging n-endo-
trig closures7 accompanied by a notable increase in ring strain
and the stringent conformational requirement for the Burgi−
̈
Dunitz angle. We envisioned that these challenges could be
efficiently addressed by employing the strain release-driven
nucleophilic addition of alkoxides and aryloxides to cyclo-
propenes developed in our laboratories.8 This methodology
takes advantage of a reactive cyclopropene intermediate 2
obtained in situ via a base-assisted 1,2-elimination of
bromocyclopropanes 1, which undergoes facile diastereo-
selective addition of oxygen,9 nitrogen,10 and sulfur-based9c
nucleophiles. We have previously reported that racemic cyclic
ethers 6 with a ring size of 7−10 can be readily accessed via the
intramolecular n-exo-trig cyclization (Scheme 1).11 Herein, we
disclose a novel 8-endo-trig nucleophilic cyclization of cyclo-
propenes 9 allowing for expeditious assembly of chiral medium
cyclic ethers 10 (Scheme 1).
the carboxamide function was shown to afford a 3,3-
disubstituted cyclopropene 5 amenable to exo-trig cyclization
(Scheme 1).11 The nonconjugated cyclopropenes 5 are
relatively stable and isolable, the downside of which is that
As mentioned above, a base-assisted 1,2-elimination of HBr
in bromocyclopropane 4 possessing a quaternary center next to
Received: October 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03068
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Letter
they undergo nucleophilic addition only with strong
nucleophiles, such as primary alkoxides. This prompted us to
explore complementary approaches to oxazabicyclo[6.1.0]-
nonanes via a highly electrophilic cyclopropene 9 capable of
reacting with a broader range of nucleophiles.9,10 It was
expected that, being strong Michael acceptors, conjugated
cyclopropenes 9 would reinforce the addition via the
mechanistically challenging n-endo-trig pathway. We envisioned
the first approach to 10 via dehydrobromination of
diastereomeric 2-bromocyclopropylcarboxamides 7, in which
deprotonation was expected to occur at the most acidic tertiary
α-CH. To test this idea, we prepared several amides 7a−e from
2-bromocyclopropylcarboxylic acid and aminoalcohols and
subjected them to powdered KOH in the presence of 18-
crown-6 ether. We were pleased to find that, in all three cases,
eight-membered cyclic ethers 10b,d,e were obtained in high
yields as sole products (Scheme 2). However, substrates
cyclopropylcarboxamides 8 possessing a quaternary center at C-
2 would give rise to conjugated cyclopropenes 9, bearing a
stereogenic center at C-3 unless R1 and R2 are identical
(Scheme 1). We anticipated that the facial selectivity of the
intramolecular nucleophilic attack would be governed by steric
factors, favoring the addition from the least hindered site.
Furthermore, the ready availability of the parent α-halogenated
cyclopropane carboxylic acids 14 in optically active form by an
efficient chiral resolution method developed in our laboratories
(Scheme 3)12 starting from routinely accessible 2,2-dibromo-
Scheme 3. Synthesis and Efficient Chiral Resolution of α-
Bromocyclopropylcarboxylic Acids
Scheme 2. Nucleophilic Ring Closures Involving
Cyclopropenes Generated from 2-Bromocyclopropane
Carboxylic Acid Derivatives
cyclopropanes 1313 makes this route very attractive for
preparation of homochiral medium-sized heterocycles 10.
Accordingly, we tested a series of racemic α-bromocyclopropyl
carboxamides 8f−i with homologous side chains under the
standard reaction conditions. Here again, bromide 8f with a
two-carbon linker (n = 0) failed to provide seven-membered
cyclization product 10f due to rapid polymerization (Scheme
4). In contrast, the bromocyclopropane possessing a three-
carbon tether (8g, Xn = CH2) underwent a very efficient 8-endo-
trig cyclization cleanly producing the corresponding oxazaca-
none 10g (Scheme 4). The 9-endo-trig cyclization of 8h (Xn =
CH2CH2) afforded a nine-membered cyclic product 10h albeit
Scheme 4. Nucleophilic Ring Closures involving
Cyclopropenes Generated from Racemic 1-
Bromocyclopropane Carboxylic Acid Derivatives
containing other than a three-carbon tether dramatically
decreased the efficiency of cyclization. Neither seven- nor
nine-membered products were detected in the corresponding
reaction mixtures of 7a and 7c. We have also explored the
possibility of an intramolecular addition of tethered aryloxides,
as phenolates have been previously employed in the
intermolecular nucleophilic addition to monosubstituted cyclo-
propenes.9a In accord with our expectations, treatment of
bromocyclopropane 11 with a base afforded nearly quantitative
yield of benzoxazocinone 12 (Scheme 2). Notably, all
annulations described above were performed using crude
mixtures of diastereomeric amides 7 at high concentration.
Inspired by these initial results, we moved on to probe a
second approach employing more challenging, densely
substituted cyclopropane precursors. In this mode, α-bromo-
B
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Letter
in low yield. Further elongation of the tether led to no success.
Attempts to cyclize 8i (Xn = OCH2CH2) resulted in
polymerization of the starting material (Scheme 3). It should
be mentioned that both cyclization products 10g and 10h were
obtained as single diastereomers with cis-orientation of the
alkoxy moiety with respect to carboxamide and methyl
substituents, indicating very efficient control of the diastereo-
selectivity by the substituents on the quaternary center.
Having mapped out the scope of ring closures to form
medium-sized rings, we proceeded to examine the 8-endo-trig
cyclization employing a series of enantiomerically enriched
substrates 8.12 It was found that a variety of substituents at the
carboxamide nitrogen were tolerated rather well, including
methyl, benzyl, p-methoxybenzyl, and furylmethyl groups
(Figure 1). N-p-Methoxybenzyl- and N-methylsubstituted
to 3,3-disubstituted or 1,3,3-trisubstituted cyclopropenes in the
intermolecular mode were unproductive. Although these
nucleophiles were previously found to be inert in the exo-trig
cyclization,9c we anticipated, however, that they would react
more readily in the endo-trig fashion with a highly electrophilic,
conjugate strained olefin. Indeed, the 8-endo-trig cyclization
reaction of bromocyclopropane 8s bearing a tethered phenol
species proceeded uneventfully affording optically active
benzazocane 10s.
The results presented above indicate that the described 8-
endo-trig ring closure has a specific, favorable trajectory of the
nucleophilic attack, in contrast to the homologous seven- and
nine-membered ring closures. In support of this hypothesis is
also the observed more sluggish reaction of 8r that can be
rationalized on the basis of the notable distortion of the Burgi−
̈
Dunitz angle imparted by the methyl substituents in the tether.
Work is underway to support this rationale by computational
methods.
Interestingly, reactions of amides generated from electron-
deficient benzylamines 8t−v did not afford cyclization products
10t−v, providing complex mixtures of oligomers instead
(Figure 1). Such a dramatic difference in reactivity of these
electron-deficient substrates as compared to electron-neutral
and electron-rich analogs, which readily provide the corre-
sponding cyclization products (ca. 10g, 10k), is not completely
understood. Further investigations of this phenomenon are
currently underway in our laboratories.
In summary, we have developed a highly diastereoselective,
intramolecular formal nucleophilic substitution of cyclo-
propanes proceeding via the 8-endo-trig addition of tethered
oxygen-based nucleophiles to in situ generated cyclopropenes.
This strategy, applied to readily available derivatives of
nonracemic 1-bromocyclopropanecarboxylic acid, provided
enantiomerically enriched oxazabicyclo[6.1.0]nonanes possess-
ing a densely substituted cyclopropane moiety with three
stereogenic centers. The disclosed protocol does not require
purification of the precursors and afforded consistently good
yields of chiral bicyclic products in the preparatively convenient
0.05 M concentration range.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03068.
Complete refs 2c and 2e; experimental procedures,
characterization data, and NMR spectral charts (PDF)
Figure 1. Intramolecular formal nucleophilic substitution of
enantiomerically enriched 1-bromocyclopropane carboxylic acid
derivatives.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mrubin@ku.edu.
ORCID
analogs were somewhat less efficient giving lower yields of
the corresponding cyclic products 10k, 10o, 10q. The steric
effect of substituents at the quaternary center of cyclopropane
was tested as well (Figure 1), using the methyl or ethyl group as
the “small” and an aryl group as the “large” substituent. In this
series, a high degree of stereocontrol was achieved for all
substrates. Even the most sterically challenging bromide 8n, in
which cyclization was forced to proceed syn to the ethyl group,
provided a respectable yield of a single product 10n.14 Our next
goal was to probe the addition of a tethered aryloxide under
these conditions. Notably, our earlier efforts to add aryloxides
Michael Rubin: 0000-0002-1668-9311
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support by the Russian
Foundation for Basic Research (Grant No. 15-03-02661).
Support for NMR instruments used in this project was
C
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Letter
M. J. Org. Chem. 2013, 78, 7601. (c) Maslivetc, V.; Rubina, M.; Rubin,
M. Org. Biomol. Chem. 2015, 13, 8993.
(11) (a) Alnasleh, B. K.; Rubina, M.; Rubin, M. Chem. Commun.
2016, 52, 7494. (b) Edwards, A.; Benin, T.; Rubina, M.; Rubin, M.
RSC Adv. 2015, 5, 71849.
(12) Edwards, A.; Ryabchuk, P.; Barkov, A.; Rubina, M.; Rubin, M.
Tetrahedron: Asymmetry 2014, 25, 1537.
(13) Sherrill, W. M.; Kim, R.; Rubin, M. Tetrahedron 2008, 64, 8610.
(14) An analogous intermolecular addition of primary alkoxides
provided the diastereoselectivity of 14:1: See ref 9d.
provided by NIH Shared Instrumentation Grant No.
S10RR024664 and NSF Major Research Instrumentation
Grant No. 0329648.
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