Templated assembly of medium cyclic ethers: Via exo-trig nucleophilic cyclization of cyclopropenes

Article abstract of DOI:10.1039/c6cc02178f

A novel method for the assembly of medium heterocycles via an intramolecular nucleophilic addition to cyclopropenes generated in situ from the corresponding bromocyclopropanes is described. The exo-trig nucleophilic cyclizations were shown to proceed very

Full text of DOI:10.1039/c6cc02178f

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DOI: 10.1039/C6CC02178F
Chemical Communications
COMMUNICATION
Templated Assembly of Medium Cyclic Ethers via exo-trig
Nucleophilic Cyclization of Cyclopropenes
Bassam K. Alnasleh,a Marina Rubina,a and Michael Rubin*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel method for the assembly of medium heterocycles via an
intramolecular nucleophilic addition to cyclopropenes generated in situ
from the corresponding bromocyclopropanes is described. The exo-trig
nucleophilic cyclizations were shown to proceed very efficiently and in a
highly diastereoselective fashion affording cis-fused bicyclic products
base
Nu
O
Nu
Br
Br
1
2
3
O
O
possessing
7
to 10-membered medium rings; starting from
a
base
O
diastereomeric mixtures of bromocyclopropanes.
XH
X
X
The abundance of medium heterocycles in nature1 and their
privileged position in drug discovery research2 generate an
increasing demand for efficient synthetic approaches to medium
rings. Medium ring closure is typically achieved via transition
metal-catalyzed3 and free radical cyclizations,4 whereas a direct
cyclization via an intramolecular addition of a nucleophilic entity has
not evolved into a practical synthetic tool. Several examples on ring
closure via lactonization5 towards 7-12 membered rings, involving a
nucleophilic attack on an activated carbonyl group have been
demonstrated. At the same time, analogous processes employing a
less reactive C=C bond are scarce.6 Although classical Baldwin’s
rules for ring closure7 do not encompass rings larger than seven, it
is commonly accepted that formation of these are disfavored.
Indeed, the free energy of such cyclizations is typically positive due
to a notable increase in the ring strain (enthalpic term) and loss of
conformational freedom (entropic term). We envisioned that both
these issues could be efficiently addressed by employing the formal
nucleophilic substitution of bromocyclopropanes 1 (Scheme 1),
which was recently developed in our labs.8 This methodology
allows for carrying out diastereoselective additions of oxygen,9
nitrogen,10 and sulfur-based9b nucleophiles to cyclopropene
intermediates 2 generated in situ via a base-assisted 1,2-dehydro-
bromination reaction.11 We envisioned the intramolecular mode of
this reaction as a convenient route for the construction of novel
types of medium heterocycles and a useful tool for expanding the
4
6
5
O
Nu'
Nu'
X
X
8
7
Scheme 1
limits of the challenging nucleophilic exo-trig medium ring closures.
The stringent enthalpic and enthropic requirements would be met
in this cyclization as the rigid cyclopropyl moiety in the molecule
backbone would endow the system with sufficient constraints,
whereas the strain energy release would allow for effective ring
closure via the nucleophilic attack of a tethered heteroatom
moiety.12 Thus, generation of cyclopropene species 5 from bromo-
cyclopropane 4 bearing a pronucleophilic moiety tethered through
the quaternary carbon would invoke an exo-trig cyclization, leading
to bicyclic scaffold 6 (Scheme 1). Furthermore, the donor-acceptor
cyclopropane with a heteroatom-based donor component in the
resulting fused system 6 has a potential for further derivatization
via ring-opening13 to furnish expanded ring systems 8 (Scheme 1).
We began by probing the assembly of seven-membered rings,
to which end we performed a test reaction of 2-ethanolamine-
derived substrates 4a,b. To our delight, both corresponding oxaz-
epanones 6a,b were formed as sole products in high yield (Scheme
2, eq 1). Similarly, 8-exo-trig, 9-exo-trig, and even 10-exo-trig ring
closures occurred uneventfully providing the corresponding bicyclic
oxazacanone (6c-f, Scheme 2, eq 2), oxazananone (6g,h, Scheme 3,
eq 6), oxazecanone (6i-j, eq 3), and dioxazecanone (6k, eq 4). The
unique feature of this sequential transformation, in which the
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COMMUNICATION
Journal Name
O
O
vacant. Considering the unusually low coordination number of the
View Article Online
Me
R
Me
R
alkali metal in these computations, the obtaiDnOedI: 1f0ig.1u0r3e9s/sCh6oCuCl0d2o1n78lyF
18-crown-6 (cat)
N
N
(1)
t-BuOK/THF
7-exo-trig
OH
K
K
Br
O
O
O
O
6a,b
Me
Me
Me
4a,b
Me
Me
N
N
N
H
4a, 6a: R = CH2CH2OH; 72%
4b, 6b: R = Cy; 91%
Me
O
O
O
6l
9
10
O
O
Me
R
Me
R
18-crown-6 (cat)
N
N
K
O
t-BuOK/THF
8-exo-trig
(2)
7-exo-trig:
boat TS1 (QST2)
b3lyp 6-311++G**
2
Br
OH
O
8
H
δ
Me
1
N
4c-f
O
δ
6c-f
5
Me
7
4c, 6c: R = Cy; 89%
4d, 6d: R = n-Hex; 84%
4e, 6e: R = Bn; 76%
ΔG‡: 18.30 kcal/mol
H
4
TS1
4f, 6f: R = anthracene-9-ylmethyl; 92%
K
O
7-exo-trig:
O
O
4
O
2
Me
8
H
δ
chair TS2 (QST2)
b3lyp 6-311++G**
ΔG‡: 32.35 kcal/mol
1
R
18-crown-6 (cat)
R
Me
N
N
O
δ
N
t-BuOK/THF
9-exo-trig
(3)
5
Me
Me
7
Br
H
TS2
4g,h
6g,h
OH
Figure 1. Geometry of two alternative transition states located for the intramolecular
7-exo-trig nucleophilic attack by tethered alkoxide 9 with pre-coordinated potassium
cation. Activation barriers are assessed for THF.
4g, 6g: R = n-Hex; 84%
4h, 6h: R = phenethyl; 86%
O
O
O
Me
R
X
18-crown-6 (cat)
N
Me
R
K
O
Me
CONMe2
N
MeOK
(4)
t-BuOK/THF
10-exo-trig
NMe2
X
MeO
Br
6i-k
11
Me
4i-k
12
HO
4i, 6i: R = Cy, X = CH2; 87%
4j, 6j: R = Bn, X = CH2; 70%
4k, 6k: R = Bn, X = O; 80%
K
O
O
H
MeO
NMe2
MeO
NMe2
- K
Me
14
Me
13
Scheme 2
reactive intermediate is generated in very low quantities, permitted
carrying out the reaction at unusually high for medium ring closure
concentrations of 0.05-0.20 M, with consistently high yields.14
Starting from diastereomeric mixtures of bromocyclopropanes 4, all
cyclizations proceeded with very high cis-diastereoselectivity,
including 9- and 10-membered ring closures of substrates bearing
very flexible tethers with no additional selectivity-inducing
elements. However, despite the efficient assembly of 7-10 memb-
ered cycles, to date, we failed to obtain 11 and 12-membered rings
via this approach.
We have previously demonstrated in our intermolecular
nucleophilic additions to cyclopropenes9c that potassium cation can
efficiently coordinate to the carboxamide functionality and direct
the addition of a nucleophilic species in syn-fashion. This directing
effect was considered in our preliminary DFT computations of 7-
exo-trig cyclization of cyclopropene 9 (Figure 1). The intermolecular
reaction (i.e., linear oligomerization and polymerization) was also
assessed by obtaining the activation barrier of the nucleophilic
addition of methoxide to cyclopropene 11 (Figure 2). To simplify
the computations, the coordination sphere of potassium, which
during the reaction is occupied by solvent molecules, was left
K
O
TS3 (QST2)
b3lyp 6-311++G**
ΔG‡: 25.19 kcal/mol
OMe
NMe2
δ
Me
δ
TS3
Figure 2. Geometry of transition state in the intermolecular nucleophilic attack of
cyclopropene 11 by methoxide anion assisted by pre-coordinated potassium cation.
Activation barrier is assessed in THF.
be used as an estimate for qualitative comparison of the two
reaction pathways.
The nucleophilic addition of methoxide8,9c commences with
the formation of coordination complex 12 and proceeds via
transition state TS3, in which potassium cation is chelated to the
alkoxide and carboxamide oxygens. The activation barrier for this
process was found to be +25.19 kcal/mol (Figure 2), while the strain
release-driven formation of zwitterionic intermediate 13 was
moderately exothermic (ΔGr = -17.58 kcal/mol). The final product,
alkoxycyclopropane 14, is obtained after protonolysis of 13 (Figure
2). Alternatively, the reaction of tethered nucleophilic alkoxide 9
produces a seven-membered zwitterionic intermediate 10, which
after protonolysis affords the corresponding oxazepanone 6l (Figure
2 | J. Name., 2012, 00, 1-3
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2
3
(a) J. G. Kettle, H. Alwan, M. Bista, J. Breed, N. L. Davies, K.
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1). Two alternative transition states, TS1 and TS2 with coordinated
potassium cation were located, as shown in Figure 1. The
calculations show the lowest energy transition state TS1 with a
pseudo-boat conformation of the bicyclic core (Figure 1).
Coordination of two oxygens to potassium does not cause any
significant distortions of the nucleophile’s trajectory in this case.
The nucleophile approaches the π-bond at a 115° angle, a slightly
larger than normal Bürgi–Dunitz angle for a trigonal attack, which is
expected for the small cycle with an increased s-character of the
strained double bond. Moreover, the shortened distance between
the potassium cation and the anionic center at C8 of cyclopropene
is responsible for an additional stabilization of this activated
complex. The activation energy of the 7-exo-trig process is calcul-
ated to be 18.30 kcal/mol, while the ΔG° of this cyclization was
found to be -5.68 kcal/mol. The significantly lower activation
energy of the cyclization compared to that of the modeled
intermolecular process (12!TS3!13, Figure 2) could explain the
favorable formation of the medium rings and lack of oligomeriz-
ation products even in relatively concentrated solutions. It should
also be mentioned that the high activation energy of the pseudo-
chair transition state TS2 (32.35 kcal/mol, Figure 1) rules out this
alternative pathway.
In conclusion, we have developed a novel method for the
assembly of medium cyclic ethers via a formal nucleophilic substit-
ution of bromocyclopropanes. An efficient exo-trig ring closure
produced 7-10 membered heterocycles with excellent cis-
selectivity. Favorable pre-organization of the acyclic precursor
augmented by the strain energy release makes this cyclization
approach highly efficient whilst offering a unique possibility for
additional stabilization of the medium ring conformation in a fused
bicyclic motif. The reaction proceeds in the unusually high for
medium ring closure concentration range, rendering this method
practical and easily scalable. DFT modeling of the 7-exo-trig
cyclization suggested the pseudo-boat TS1 as the likely structure of
the reaction transition state. The three-prong coordinated
potassium plays a crucial role in stabilization of the newly forming
bicyclic core, making this model potentially suitable for predicting
the results of diastereoselective cyclizations. Further studies are
currently underway in our laboratories, aiming at (1) extending this
methodology to the synthesis of larger ring systems; (2) employ-
yment of tethered chiral nucleophilic entities for diastereoselective
ring closure; (3) probing N-, C-, and S-based nucleophiles for furn-
ishing other types of medium heterocycles; (4) evaluating endo-trig
mode of the ring closure.
Eckersley, S. Fillery, K. M. Foote, L. Goodwin, D. R. Jones, H. Käck,
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12 For assembly of 8-membered heterocycles via 4+4 cyclodimer-
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13 See, for example: V. Maslivetc, M. Rubina, M. Rubin, Org.
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We are grateful for the financial support by the Russian
Foundation for Basic Research (grant #15-03-02661). Support
for NMR instruments used in this project was provided by NIH
Shared Instrumentation Grant #S10RR024664 and NSF Major
Research Instrumentation Grant #0329648.
Notes and references
14 See Supporting Information for details.
1
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M. K. Sano, L. S. Longo, Jr., Quim. Nova 2008, 31, 885. (c) M. A.
Ciufolini, Farmaco 2005, 60, 627.
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