Stereo- A nd regioselective synthesis of molecular baskets

Article abstract of DOI:10.1021/acs.joc.9b00330

We describe a stereoselective method for obtaining multigram quantities of molecular basket 1_syn in overall 11% yield, using inexpensive cyclopentadiene and diethyl fumarate as starting materials. First, an asymmetric synthesis of enantioenriched bromo(trimethylstannyl)alkene (-)-8 was accomplished by the stereoselective bromination of dibromonorbornene (+)-4 guided by anchimeric assistance and subsequent syn-exo-elimination of tetrabromonorbornane (-)-5a as the key steps. Subsequent Cu(I)-catalyzed cyclotrimerization of (-)-8 was optimized to give 1_syn/anti in 85% yield and 1:1 ratio of diastereomers. Importantly, the results of our mechanistic experiments were in line with the cyclotrimerization occurring in a chain-type fashion with racemization of a Cu(I) homochiral dimeric intermediate, reducing the stereoselectivity of the transformation. Enabled by more facile access to molecular baskets of type 1_syn, a range of recognition studies can now be completed for producing novel supramolecular catalysts, organophosphorus scavengers, and nanostructured materials.

Full text of DOI:10.1021/acs.joc.9b00330

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Article
Stereo- and Regioselective Synthesis of Molecular Baskets
Michael J Gunther, Radoslav Z Pavlovic, Joseph P Fernandez, Lei
Zhiquan, Judith Gallucci, Christopher M. Hadad, and Jovica D. Badjic
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00330 • Publication Date (Web): 15 Mar 2019
Downloaded from http://pubs.acs.org on March 17, 2019
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Page 1 of 11
The Journal of Organic Chemistry
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Stereo- and Regioselective Synthesis of Molecular Baskets
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Michael J. Gunther, Radoslav Z. Pavlović, Joseph P. Fernandez, Lei Zhiquan, Judith Gallucci, Christo-
pher M. Hadad and Jovica D. Badjić*
0
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0
Department of Chemistry and Biochemistry, The Ohio State University, 100 W. 18th Avenue, Columbus, Ohio 43210, Unit-
ed States
ABSTRACT: We describe a stereoselective method for obtaining multigram quantities of molecular basket 1syn in overall 11%
yield, using inexpensive cyclopentadiene and diethyl fumarate as starting materials. First, an asymmetric synthesis of enantioen-
riched bromo(trimethylstannyl)alkene (−)−8 was accomplished by stereoselective bromination of dibromonorbornene (+)−4 guided
by anchimeric assistance, and subsequent syn-exo-elimination of tetrabromonorbornane (−)−5a as the key steps. Subsequent Cu(I)-
catalyzed cyclotrimerization of (−)−8 was optimized to give 1syn/anti in 85% yield and 1:1 ratio of diastereomers. Importantly, the
results of our mechanistic experiments were in line with the cyclotrimerization occurring in a chain-type fashion with racemization
of a Cu(I) homochiral dimeric intermediate reducing the stereoselectivity of the transformation. Enabled by a more facile access to
molecular baskets of type 1syn, a range of recognition studies can now be completed for producing novel supramolecular catalysts,
organophosphorus scavengers and nanostructured materials.
Introduction
into 1syn in 24% yield, albeit providing 61% of undesired 1anti
Figure 1). This begged a question: is such Cu(I)-catalyzed
(
Molecular baskets with α-amino acids at their periphery
possess hydrophobic pockets (Figure 1) that are complemen-
tary to tetrahedral organophosphorus (OP) compounds. These
18
transformation regioselective so that enantiopure 8RS (Figure
19
1
1) can be exclusively turned into 1syn? As the mechanism of
2
copper-catalyzed Stille couplings and cyclotrimerizations re-
C
3
symmetric hosts are responsive to light, and after decar-
2
0
mains debatable, we, for the sake of argument, began our
boxylation, they assemble into organic nanoparticles which we
have probed for spatiotemporal sequestration and/or degrada-
2
1
reasoning with the formalism in which transmetallation of
2
2
3
4
CuI and trimethylstannyl 8RS gives nucleophilic RCu that, via
oxidative addition, reacts with Csp2−Br of another 8RS (Figure
1). After reductive elimination, the sequence ought to be re-
peated to furnish the annulation. Importantly, the postulated
chain-type mechanism would require more than one molar
equivalent of Cu(I) due to, perhaps, reversible and thermody-
tion of OP nerve agent simulants and pesticides. Further-
more, baskets are complementary to small hydrocarbons from
5
6
7
8
natural gas, haloalkanes, ammonium cations, fullerenes and
9
other functional molecules. As a result, one could envision
their future development into (a) supramolecular and ”green”
catalysts capable of converting hydrocarbon gases into feed-
20a
1
0
namically unfavorable transmetallation step. As the homo-
stock chemicals under mild conditions, (b) micro-to-
mesoporous materials for storage of gases and/or sequestration
chiral couplings of enantiopure 8RS are expected to give 1syn
both homochiral and heterochiral couplings of racemic 8RS/8SR
(Figure 1) could take place simultaneously to give 1syn and
,
1
1
of pollutants, and (c) surface-based devices for detection of
12
toxic analytes. The concave framework of baskets has also
been used in the preparation of carbon-based materials, the
examination of unusual chemical bonds, and the study of
gated molecular encapsulation.
13
1
anti. If the rates of competing reactions are comparable
18
14
(though, not necessarily the case), the expected ratio of
syn/1anti becomes statistical (1:3). In this respect, De Lucchi
and coworkers showed that copper(I) thiophene-2-carboxylate
CuTC) could be used to promote regio- and stereoselective
1
5
1
In order to facilitate and broaden the scope of fundamental
and application-oriented studies, a more effective way for
accessing larger quantities of baskets is needed. Indeed, we
recently reported an improved methodology for preparing the
common precursor of baskets 1syn (Figure 1), with 6.9 g (70
mmol) of maleic anhydride giving 0.5 g of this hexa-ester in
overall 3% yield. In the key synthetic step, CuI-catalyzed cy-
clotrimerization of racemic bromo(trimethylstannyl)alkene 8
(
1
6
cyclotrimerizations for a limited number of enantiopure nor-
19
1
7
bornenes. Furthermore, Lin and Wang used density function-
al theory to examine CuTC-promoted Stille coupling of vi-
nylstannane and vinyl iodide, thereby reporting that the trans-
formation occurs by a mechanism similar to the one shown in
21
Figure 1.
Finally, Sakurai and coworkers dis
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Page 2 of 11
MeO2C
CO2Me
MeO2C
CO2Me
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
anti
1
syn
MeO2C
MeO2C
CO2Me
CO2Me
MeO2C
MeO2C
CO2Me
CO2Me
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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0
1
2
3
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9
0
1
2
3
4
5
6
7
8
9
0
Molecular Basket Tabun
MeO2C
CO2Me
MeO2C
CO2Me
R
MeO2C
MeO2C
Sn(Me)3
Br
8SR
R
CuI
8
RS
S
S
8RS
(Me)3SnI
S
R
Br
Sn(Me)3
transmetallation
Br
(Me)3Sn
Sn(Me)3
Br
(Me)3Sn
Br
MeO2C
MeO2C
Cu
Br
MeO2C
MeO2C
MeO2C
MeO2C
CO2Me
CO2Me
CO2Me
CO2Me
reductive
elimination
oxidative
addition
(Me)3Sn
Br
Br
8RS
Cu
CuBr
MeO2C
MeO2C
CO Me
2
CO Me
2
Figure 1. (Top right) Energy-minimized (MMFF, Spartan) structure of a molecular basket with three (S)-Glu residues holding the
OP nerve agent tabun (van der Waals surface, Chimera) in its hydrophobic pocket. (Left and Bottom) A chain-type mechanism for
CuI-promoted homochiral coupling of enantiopure 8RS into 1syn. With a racemic mixture of 8RS and 8SR (red) and comparable rates
of competing homochiral and heterochiral couplings, the ratio of 1syn to 1anti is statistical (1:3); in line with this, obtaining any other
ratio of 1syn/1anti stereoisomers is hereby referred to as stereoselective.
(
A)
Br
CO Me
2
stannylation Br
CO Me Diels Alder Br
2
Me Sn
CO Me
3
2
CO Me
oxidation
2
8
7
6
exo
E2
Stereoselective
bromination via
reduction
substitution
Br anchimeric
assistance
H
Br
EtO C
2
Diels Alder
CO Et
2
Br
+
CO Et
CO Et
2
2
Br
Br
Br
2
4
5
(B)
Br
Br
Br
Br2
Br
Br
4-II
Br
Br
Br
4
4-I
Br
Scheme 1. (A) Retrosynthetic scheme for obtaining enantiopure 8. (B) A postulated mechanism for electrophilic bromination of 4.
covered that palladium nanoclusters could be used for the
preparation of a few substituted syn-benzocyclotrimers via
stereoselective Heck couplings of enantiopure iodonor-
23 16-17
bornenes. Encouraged by these and our
findings and the
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The Journal of Organic Chemistry
2
4
notion that regio- and stereoselective cyclotrimerization of
enantiopure norbornenes could, in some cases, be realized, we
set out to investigate the first asymmetric synthesis of enanti-
6, we anticipated that E2 elimination of 5 should preferen-
tially occur on the exo side of this tetrabromo norbornane. On
1
2
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4
5
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
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2
2
2
2
2
2
3
3
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3
3
3
3
4
4
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
4
the basis of an earlier study, we then hypothesized that regio-
Ph
(
A)
Ph
O
B
O
TfO
N
LiAlH4
OH
OH
EtO C
H
OEt
OEt
2
+
THF / 0 ºC
95%
CH Cl / -35 ºC
2
2
CO Et
2
98%, 99% ee
O
(-)-3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(+)-2
Br
Br
1
. MsCl / Et N
CH Cl / 0 ºC
CBr / PPh
Br
Br
3
4
3
/
5b
2
2
TBAB
3
2
2. LiBr / THF / Δ
7%
70%
1
.969 A
8
b
1
.953 A
(minor)
2
Br
Br
Br 3
Br
2
/ CH
Cl
2 2
Br
Br
1
-78 ºC
Br
Br
a
2
Br
(major)
Br
85%, 12:1
(
-)-5a
Br
(+)-4
t-BuOK
THF / 0 ºC
Br
CO Me
2
Br
CO Me
Br
2
1. DMAD / PhMe / Δ
. DDQ / CH Cl
1. LDA / THF / -78 ºC
2
. Me SnCl / THF
3
2
CO Me
2
2
2
(Me) Sn
CO Me
3
2
7
5%, 98% ee
60%, 96% ee
(-)-8
6
(-)-7
(B)
5 mol% Pd(OAc)2
10 mol% Ph
H
N
P
3
Br
CO Me
N
H
I
CO Me
2
2
1
0 molar equiv. n-Bu NOAc
4
No Reaction
1
0 molar equiv. Na CO3
MS 4A
1,4-dioxane / 100 ºC
NaI / CuI
91%, 98% ee
2
CO Me
CO Me
2
2
(-)-7
(
-)-9
Figure 2. (A) Stereoselective synthesis of bromo(trimethylstannyl)alkene (−)−8. Solid-state structure of tetrabromo compound (−)−5a.
B) Cyclotrimerization of (−)−9 with palladium nanoclusters.
(
opure 8 and its conversion into desired 1syn using CuI as a cata-
and stereoselective bromination of norbornene 4 should, via
anchimeric assistance, give enantiopure 5 (Scheme 1B). In line
1
8
lyst. We posited that if we developed a preparative method
for obtaining larger quantities of enantiopure 8, we should
facilitate efforts toward optimizing its cyclotrimerization into
2
4
with the proposed mechanistic scenario, the exo addition of
bromine to 4 leads to three-membered bromonium 4-I that
after a regioselective opening, by the juxtaposed bromometh-
ylene from the endo side of the norbornane, rearranges into the
more stable five-membered bromonium 4-II. Ensuing SN2
attack by bromide on the primary carbon in 4-II furnishes
enantiopure 5. And finally, enantioselective Diels-Alder reac-
tion of cyclopentadiene and diethyl fumarate (DEF) should
give bis-ester 2, which after reduction and substitution was
expected to form the dibromo 4 (Scheme 1A).
the desired 1syn
.
Results and Discussion
As described in our retrosynthetic analysis in Scheme 1A,
compound 8 could be obtained from 6 by Diels-Alder reaction
followed by oxidation and stannylation of enantiopure 7 under
2
5
17
established conditions. To prepare enantiopure bromotriene
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Following our retrosynthetic scheme, we used chiral and
tatory (+)−2 in tetrahydrofuran led to the formation of the ex-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
commercially available oxazaborolidine catalyst (Figure 2A)
to differentiate two enantiotopic faces of DEF which in the
reaction with cyclopentadiene gave (+)−2 in excellent 98%
pected bis-alcohol (−)−3 in 95% yield. An alternate and
cheaper method for obtaining enantiopure 3 that utilizes a
Diels-Alder reaction between (−)-dimenthylfumarate and cy-
2
5
27
27a
yield with 99% ee. The reaction can be run on a large scale
(12 g of DEF), to give 16 g of practically enantiopure (+)−2
with its absolute configuration established by Seebach and
clopentadiene, in the presence of Et AlCl or SnCl as Lew-
2
4
26
is acids, has been reported. A diastereomeric cycloadduct
dominates the reaction’s outcome (>95% de), which after re-
duction gives desired bis-alcohol in overall 65% yield (due to
2
6
coworkers. Lithium aluminum hydride reduction of dextroro-
(A)
(B)
MeO
2
C
2
MeO C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1.00
CO
2
Me
Br
CO Me
CuI / DMF / DME
LiNO / 298 K
0.75
2
3
CO
2
Me
(Me)
3
Sn
CO
2
Me
0.50
0.25
(-)-8
1syn : 1anti = 1 : 1
MeO
2
C
CO
2
Me
0
20 40
60
80 100
ee of (-)-8 (%)
(C)
(D)
Br
Sn
CO Me
2
(-)-8
Sn(Me)
3
CuI
(Me) SnI
LiNO
3
(Me)
3
2
CO Me
Cu
2
CuONO Li
+
Br
-)-8
3
Br
Br
(
Br Br
transmetallation
CO
2
Me (+)-10
Sn(Me)
3
MeO
2
C
MeO
2
C
CO Me
2
Br
(Me) SnONO
3
2
(-)-8
CuI / DMF / DME
LiNO
3
/ 298 K
1
syn (1) + 1anti (1.2)
(+)-10
87% recovered
Sn(Me)
3
Sn(Me)
3
+
(
I)
66%
(
Cu
III)
(-)-8
Br
Cu
Li
(E)
Br Br
Br Br
LiBr
oxidative
addition
Br
Sn
CO
CO Me
Me
2
reductive
elimination
(-)-8
Me
3
2
1
anti
CuI
3
Me SnI
3
(Me) SnBr
Br
Br
CO Me
2
CO
2
Me
H+
Sn(Me)
3
Sn(Me)
Br
3
CO Me
Cu
CO Me
2
2
(I)
Cu
(-)-7
Br
Br
CO Me
2
Br
Cu
CO Me
2
CuBr
11
CO Me
2
CO Me
2
Cu
12
Br
(F)
(-)-8
1
anti
5
4
0
CO
2
Me
H+
Cu
CO Me
2
0
Br
CO Me
Br
CO Me
2
2
1
syn
(+)-7
30
2
0
0
0
%
compound
SnMe
Br
3
CO
2
Me
1
(+)-8
CO Me
2
(-)-7
0
2
4
6
8
10 12 14 16 18 20
time (min)
Figure 3. (A) Cu(I) catalyzed cyclotrimerization of enantioenriched (−)−8 (96% ee) gave both 1syn and 1anti in equal ratio. (B) A
1
plot showing the product ratio of 1syn/1anti ( H NMR spectroscopy) as a function of enantiopurity (ee) of (−)−8 used in the cyclot-
rimerization (CuI, DMF). (C) A cyclotrimerization mechanism occurring via homochiral Sn−to−Sn coupling of (−)−8. (D) Cu(I)
catalyzed cyclotrimerization of enantioenriched (−)−8 in the presence of homochiral dimer (+)−10. (E) Postulated mechanism for
1
the racemization of (−)−8. (F) We used H NMR spectroscopy and HPLC chromatography (Figure S28) to monitor the progress of
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Page 5 of 11
The Journal of Organic Chemistry
the lower yield, we refrained from using this synthetic alterna-
tive). After mesylation (92%) of (−)−3 and S 2 substitution of
note that racemic 9 was, under the same reaction conditions,
also found to be unreactive.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
N
the mesylate with lithium bromide (95%), we obtained (+)−4.
Indeed, the conversion of (−)−3 into dextrorotatory (+)−4
could be completed in a single step using the Appel reaction,
but we encountered difficulties with the reaction’s reproduci-
bility and product isolation. The low temperature bromination
of (+)−4 in dichloromethane gave two diastereomeric products
in 12:1 ratio and overall 85% isolated yield (Figure 2A). The
Next, we examined the CuI-catalyzed cyclotrimerization of
1
8
enantioenriched (−)−8 (96% ee, Figure 3A) in DMF follow-
1
7
ing our earlier established protocol. As a reminder, in the
CuI-catalyzed reaction, racemic 8 would form 1syn /1anti in 84%
yield with a 1:2.5 ratio of diastereomers. However, enantioen-
riched (−)−8 (96% ee, Figure 3A) was found to give 1syn /1anti
in similar 85% yield but with a 1:1 ratio of diastereomers.
1
1
major product (−)−5a ( H− H NOESY and COSY, Figures
S16-17) formed via the neighboring group participation of the
endo bromomethylene (pathway a, Figure 2; see also Scheme
Moreover, reducing the enantiopurity of (−)−8 was found to
have a steady and adverse effect on the quantity of the desired
syn diastereomer formed in the process, as depicted with the
linear relationship in Figure 3B. In line with the chain-type
mechanism (Figure 1), the enantiopure 8 should, via homochi-
ral Sn−to−Br couplings, lead to the exclusive formation of the
syn diastereomer, which clearly was not the case. On the other
hand, following the mechanism for Cu(I)-catalyzed cyclotri-
merizations proposed by De Lucchi and coworkers (Figure
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
1
). On the other hand, the minor product 5b ( H− H COSY,
Figure S19) formed by the opening of the bromonium cation
via endo attack of the external bromide on carbon 2 (pathway
b in Figure 2A) – note that the bromomethylene group on the
exo side is unable to participate in the anchimeric assistance.
The same type of competition (pathways a and b in Figure 2A)
was observed in electrophilic selenylation and sulfenylation of
2
0b
3
C), the homochiral coupling of (−)−8 ought to exclusively
2
4
norbornenes for which more persistent onium cations medi-
ated the transformation. The base-promoted elimination of
yield 1anti, which also did not take place. In line with this
mechanistic scenario, the Italian team reported that enantioen-
riched substrates would often give homodimers along with a
(
−)−5a gave volatile and reactive bromotriene 6, which in the
1
8, 31
cycloaddition with dimethyl acetylenedicarboxylate (DMAD)
and subsequent DDQ oxidation, formed (−)−7 in 75% yield
greater quantity of the anti-cyclotrimer.
In light of the
arguments above, the linear dependence in Figure 3B could be
interpreted by rendering mechanisms in Figures 1 and 3C as
either inapt or incomplete. Accordingly, we noted that in the
(
(
98% ee). With stereoselective conversion of enantioenriched
+)−4 into (−)−7 (Figure 2A), we surmised that synthesized 5a
ought to be enantioenriched as well. Moreover, the X-ray crys-
tal structure of (−)−5a (Figure 2A) corroborated its absolute
configuration thereby providing evidence for the proposed
mechanism of rearrangement. To elucidate the absolute con-
figuration of (−)−7, however, we noted that syn-periplanar E2
elimination of (−)−5a could be occurring on either the exo or
cyclotrimerization of (−)−8 there was no detectable formation
1
( H NMR spectroscopy) of the C
2
-symmetric and homochiral
18, 20b
dimer 10 (Figure 3D).
To additionally examine the role of
10, and the mechanism in Figure 3C, we synthesized this mol-
ecule by completing Sn−to−Sn coupling of (−)−8 using
3
2
2
Cu(OTf) . When one molar equivalent of (+)−10 was added
endo side of the norbornane framework. In this regard, the
to three molar equivalents of (−)−8 (Figure 3D) and the mix-
ture subjected to CuI in DMF, the catalytic conversion took
place giving 1syn/anti = 1:1.2 in 66% yield with (+)−10 almost
fully (87%) recovered. A rather insignificant effect of the ho-
modimer (+)−10 on the reaction’s outcome can, perhaps, be
interpreted by this molecule not participating in the cyclotri-
merization to favor chain-type (Figure 1) over the Sn−to−Sn
exo
2
solid-state structure of (−)−5a shows that C −Br (1.969 Å,
endo
Figure 2A) is longer than C
3
−Br
(1.953 Å, Figure 2A) and,
perhaps, easier to break in the elimination. Secondly, the exo
elimination was already observed to prevail with a norbornane
2
4
compound akin to 5.
To probe if the anticipated (−)−7 in Figure 2A formed, we
2
0b
2
8
(
Figure 3C) mechanistic alternative. If enantiopure (−)−8
computed its specific rotation [α]
D
.
Using molecular me-
were to racemize (Figure 3E), however, both 1syn/anti would be
forming as the time progresses regardless of the mechanism.
In this regard, a departure of CuBr from Cu(I)-norbornene
chanics, we determined the diverse conformations that con-
tributed to the Boltzmann distribution, and then re-optimized
each of these structures with density functional theory
33
could give bicyclo[2.2.1]heptyne 11 (Figure 3E) in equilibri-
(
B3LYP with 6-31+G(d) for C, H, and O and 6-311+G(2d) for
Br). The six energy-minimized conformers (derived from the
Boltzmann populations) of (−)−7 had [α] = −46.3, which is in
good agreement with the experimental value of −48.8. In a
similar manner, we found that computed [α] values of chlo-
34
um with achiral Cu(I) carbene complex 12, which then turns
back into enantiomer (+)−8; note that related palladium-
D
3
5
containing intermediates occur in cine substitutions. In sup-
33
port of the racemization, Gassman and coworkers discerned
the formation of highly-strained bicyclo[2.2.1]heptyne (nor-
bornyne) akin to 11. More recently, Gilbert and coworkers
D
ro- (16, Table S2) and iodonorbornenes (9, Table S2) ana-
logues of (−)−7 agreed with the experimental values as well.
3
4, 36
demonstrated
that norbornyne acts more as a dicarbene
Finally, the stannylation of (−)−7 occurred with the reten-
tion (Figure S28) to give (−)−8 in 60% yield (96% ee). When
that is in equilibrium with alkylidenecarbene 12 (Figure 3E).
Both Komatsu’s and Hart’s research groups confirmed the
3
7
5
a/5b = 12:1 mixture (84% de) was used in the synthesis (vide
transient formation of bicyclo[2.2.2]octynes by trapping
38
infra), we obtained enantioenriched (−)−8 (84% ee).
them with 1,3-diphenylisobenzofuran. To probe if the pro-
To probe the preparation of 1syn (Figure 1) using palladium
posed racemization of (−)−8 (84% ee, Figure 3E) occurred in
the cyclotrimerization, we set five simultaneous reactions to
take place under identical conditions. Each reaction was ter-
minated at different time, and the reaction mixtures subjected
29
nanoclusters, we proceeded with the synthesis of enantioen-
riched iodonorbornene 9 (Figure 2B). In Cu(I)-catalyzed ex-
30
change of bromide with iodide, compound (−)−7 was con-
1
to HPLC and H NMR analyses to reveal a gradual disappear-
verted into (−)−9 with the retention (Table S2) of configura-
tion (91%, 98% ee). However when (−)−9 was subjected to
ance of (−)−8 with the concomitant formation of 1syn and 1anti
(Figure 3F). In addition, the appearance of (−)−7 manifested
2
3
cyclotrimerization, we only recovered the starting material;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 11
the transient formation of copper(I)-transmetallated (−)−8 (that In an attempt to optimize the cyclotrimerization of (−)−8 for
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was protonated during the work-up) at a steady state concen-
tration. Importantly, both enantioenriched (−)−8 and (−)−7
persisted (84% ee) for the entire course of the reaction there-
fore refuting the anticipated racemization of the reactant and
its transmetallated product! Can another intermediate from
two mechanisms under consideration (Figure 1 and 3C) un-
dergo racemization? For the mechanism starting with Sn-to-Sn
obtaining more of 1syn, we ran the reaction at various tempera-
tures (Figure 4B/C). First, we noted that the yields of 1syn/anti
showed a similar parabolic dependence with temperature for
both enantioenriched (96% ee) and racemic 8 (Figure 4B). It
follows that homochiral and heterochiral couplings of (+) and
(−) enantiomers of 8 occur at comparable rates with a small
degree of enantiomeric discrimination: each enantiomer
chooses its coupling partner with no particular preference re-
2
0b
homocoupling of (−)−8 (Figure 3C), it is difficult to envi-
sion any of intermediates undergoing a facile loss of stereo-
1
8
sulting in similar quantity of diastereomeric 1syn/anti products.
chemical information. On the contrary, the chain-type cyclot-
Furthermore, for racemic 8, the diastereomeric syn/anti prod-
uct ratio did not change with temperature and was close to the
expected statistical value of 0.33 (Figure 4C). However, in the
cyclotrimerization of enantioenriched 8, the yield of 1syn was
higher and showed a parabolic dependence with temperature
(Figure 4C). First, we reason that at a room temperature, ho-
mochiral and heterochiral 13/15-to-(−)−8 couplings could (in
accord with Figure 4A) dominate the reaction’s outcome to
give roughly 1:1 ratio of products. Next, we noted lower yields
of diastereomeric 1syn/anti at temperatures below and above 298
K (Figure 3D). With more extensive and “non-productive”
depletion of (−)−8, additional reaction channels may open to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
20a, 20c, 21
rimerization
(Figure 4A) could occur via 13 undergo-
ing an intramolecular oxidative addition to give meso Cu(III)
4
0
metallacyclopentadiene 14. Following, reductive elimina-
tions from 14 produce racemic 13/15 from which 1syn and 1anti
are, respectively, generated. A faster formation of 1syn over
1
anti early in the transformation (Figure 3F) could have resulted
from relatively slow conversion of 13 into 15 permitting the
initial build up of the desired syn product. Indeed, providing
experimental evidence for 13 and learning about its racemiza-
tion (Figure 4A) is an objective worth pursuing for perfecting
the synthetic procedure.
(A)
Br
CO Me
Br
CO Me
CuI
Br
CO
2
2
Me
Me
2
2
(-)-8
Br
oxidative
addition
Me Sn
CO Me
Me SnI
3
Cu
CO
Cu
CO Me
2
3
2
Me Sn
3
(-)-8
Br (III)
Cu
CO Me
2
reductive
elimination
CO Me
2
1
4
MeO C
CO Me
2
2
Br
Me Sn
Br
CO Me
2
Cu
CO Me
Br
CO Me
2
2
Cu
MeO C
CO Me
2
2
3
Br
Cu
CO Me
2
CO Me
CO Me
2
2
(-)-8
(-)-8
1
5
13
1anti
1syn
MeO
2
C
CO Me
2
MeO C
CO Me
MeO C
CO Me
2
2
2
2
(B)
racemic 8
enantienriched (-)-8 (96% ee)
(C)
racemic 8
enantioenriched (-)-8 (96% ee)
90
1.0
.8
8
0
(%)
0
70
60
50
syn/anti
0.6
0.4
1
d
l
e
Y
i
0
.2
0
10 20
Temperature (ºC)
30 40
50
0
10 20
30 40 50
Temperature (ºC)
Figure 4. (A) A chain-type mechanism for CuI-promoted cyclotrimerization of enantiopure (−)−8 with homochiral dimer 13 un-
dergoing intramolecular oxidative addition to give achiral (meso) Cu(III) intermediate which after a reductive elimination forms
enantiomeric 14. (B) A plot showing yields of 1syn/anti as a function of temperature for cyclotrimerizations of enantioenriched (red)
and racemic (blue) 8. (C) Ratio of 1syn/1anti as a function of temperature from cyclotrimerizations described in (D).
ACS Paragon Plus Environment

Page 7 of 11
The Journal of Organic Chemistry
stereoisomer −) and 95.4 mins (major stereoisomer +). [ꢀ]! +103 (c
"
steer the reaction’s diastereoselectivity toward 1anti (Figure
!
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3E).
= 1.00, CHCl
(
(
3
).
(1R,2S,3S,4S)-bicyclo[2.2.1]hept-5-ene-2,3-diyl)dimethanol
−)−3: To a suspension of lithium aluminum hydride (3.10 g, 81.7
Conclusion
mmol) in THF (80 mL) at 0 °C, a solution of compound (+)−2 (5.00
g, 21.0 mmol) in THF (50 mL) was added dropwise. The resulting
solution was warmed to 25 °C and stirred for 30 minutes. The solution
was cooled to 0 °C and then quenched with aqueous NaOH (3 mL, 3.5
M). Ethyl acetate (20 mL) and water (20 mL) were added followed by
filtration through a pad of celite. The organic filtrate was dried with
In conclusion, we developed regio- and stereoselective
methodology for obtaining molecular baskets of type 1syn. In
the key synthetic step, Cu(I)-catalyzed cyclotrimerization of
enantioenriched bromo(trimethylstannyl)norbornene (−)−8
gave cup-shaped 1syn in 43% yield. Following our optimized
procedure, one can now use 12 g (70 mmol) of inexpensive
diethyl fumarate and, in roughly two weeks, obtain 1.8 g of
basket 1syn (9%). Due to difficulties in chromatographic sepa-
ration of (−)−5a and 5b (Figure 2), however, we realized that
completing the synthesis with (−)−5a/5b mixture (12:1, Figure
2) would give 2.0 g of 1syn (11 %); the preparative route for
using (−)−5a/5b mixture is described in the experimental sec-
tion. With more facile access to gram quantities of functional-
ized molecular baskets, the stage is now set for broadening the
scope of experimental studies toward creating novel catalysts,
OP scavengers and nanostructured soft materials.
Na
2 4
SO and concentrated in vacuo to give 3.20 g of (−)−3 as a clear
1 13
oil (95%). H NMR and C NMR data corresponding to this com-
4
1 1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
pound were in line with the literature. H NMR (400 MHz, CDCl
δ (ppm) 6.23 (dd, J = 3.20, 5.47 Hz, 1H), 5.98 (dd, J = 2.76, 5.54 Hz,
3
):
1
1
2
H), 3.77 (dd, J = 5.52, 9.75 Hz, 1H), 3.66 (dd, J = 5.23, 9.72 Hz,
H), 3.42 (t, J = 9.95 Hz, 1H), 3.03 (t, J = 9.85 Hz, 1H), 2.82 (s, 1H),
.59 (s, 1H), 1.91–1.96 (m, 1H), 1.45 (bs, 2H), 1.28–1.33 (m, 1H).
13
1
3
C{ H} NMR (100 MHz, CDCl ): δ (ppm) 138.0, 133.4, 66.5, 66.0,
!"
3
47.9, 47.1, 46.9, 44.6, 44.5. [ꢀ]! = −23.9 (c = 1.00, CHCl ).
(1R,4S,5S,6S)-5,6-bis(bromomethyl)bicyclo[2.2.1]hept-2-ene
(+)−4: To a solution of freshly distilled Et N (36 mL, 260 mmol) and
2 2
bis-alcohol (−)−3 (10.0 g, 65 mmol) in dry CH Cl (260 mL), MsCl
(20 mL, 260 mmol) was added dropwise at 0 °C. The reaction was
allowed to warm to room temperature to be stirred overnight. The
3
reaction mixture was then cooled to 0 °C and quenched with H
100 mL), extracted with CH Cl (3 x 100 mL), washed with
NaHCO , dried with Na SO , and concentrated in vacuo to give 18.5
g of the crude mesylate as a brown oil (R
2
O
Experimental Section
(
2
2
General Information. All chemicals were purchased from com-
mercial sources and used as received unless stated otherwise. All
solvents were dried prior to use according to standard literature pro-
cedures. Chromatographic purifications were performed with silica
3
2
4
f
= 0.38; on SiO1
2
2
chromatographic plates with hexanes:ethyl acetate = 1:1; I stain). H
NMR (600 MHz, CDCl ): δ (ppm) 6.30 (dd, J = 5.7, 3.2 Hz, 1H), 6.11
3
gel 60 (SiO
2
, Sorbent Technologies 40-75 µm, 200 x 400 mesh).
(dd, J = 5.7, 2.9 Hz, 1H), 4.24 (ddd, J = 18.0, 9.9, 7.6 Hz, 2H), 3.97
(dd, J = 7.9, 1.2 Hz, 2H), 3.04 (s, 3H), 3.01 (s, 3H), 3.00-2.97 (m,
1H), 2.81-2.78 (m, 1H), 2.17-2.12 (m, 1H), 1.60-1.56 (m, 1H), 1.51–
1.44 (m, 2H). C{ H} NMR (150 MHz, CDCl
134.1, 72.5 (2C), 46.5, 44.4, 44.2, 43.7, 43.1, 37.7, 37.6. HRMS (ESI-
MS): m/z calcd for C11 Na: 333.0437 [M+Na]+; found:
333.0425. The mesylate (10.70 g, 34.5 mmol) was disolved in THF
(320 mL) and LiBr (38.50 g, 443 mmol) was added in one portion.
The susspession was heated at reflux for 8 h. The reaction was cooled
Thin-layer chromatography (TLC) was performed on silica-gel plate
w/UV254 (200 µm). Chromatograms were visualized by UV-light or
stained with I
tubes (Wilmad Lab Glass). NMR experiments were performed with
Bruker 400, 600, 700 and 850 MHz spectrometers. Chemical shifts
are expressed in parts per million (δ, ppm) while coupling constants
13
1
2
. All NMR samples were kept in class B glass NMR
3
): δ (ppm) 138.3,
18 2 6
H S O
(
J) are given in Hertz (Hz). Residual solvent protons were used as
1
internal standards: for H NMR spectra CDCl
3
= 7.26 ppm while for
was purchased from
13
C NMR spectra CDCl
3
= 77.2 ppm; CDCl
3
and concentrated in vacuo. The oil was dissolved in CH
washed with water. Organic layer was dried with Na SO and concen-
trated in vacuo to give 15.8 g of (+)−4 as a yellow oil (87%); R =
2 2
Cl and
Cambridge Isotope Laboratories. High-resolution mass spectra
HRMS) were obtained using positive electron impact (EI), chemical
2
4
(
f
ionization (CI) recorded on a VG 70-VSE(B) instrument or positive
electrospray ionization techniques (ESI) recorded on a Bruker-ESI
TOF instrument. Optical rotation was measured on a Perkin-Elmer
241 Polarimeter (c is in g/100 mL and the path length was 1 decime-
ter). Enantiomeric excesses of chiral compounds were determined by
either chiral stationary phase gas chromatographic (CSP GC) or high
performance liquid chromatography (HPLC) analysis. CSP GC was
performed on an Agilent 7820A using hydrogen as the carrier gas,
equipped with a Cyclosil-B (30 m x 0.25 mm, 0.25 µm film thick-
ness), capillary GC columns purchased from Agilent. Each GC was
equipped with FID detectors and integrators or a computer. HPLC
was performed on an Agilent 1260 Infinity II Quaternary LC, using
Chiralpak AD-H column (250 x 4.6 mm, 5 µm particle size) eluting
0.82 on SiO chromatographic plates with hexanes:ethyl acetate = 6:1.
2
1
H NMR (600 MHz, CDCl ): δ (ppm) 6.31 (dd, J = 5.7, 3.2 Hz, 1H),
3
6.13 (dd, J = 5.7, 2.9 Hz, 1H), 3.56 (dd, J = 9.8, 7.5 Hz, 1H), 3.39 (dt,
J = 9.7, 7.6 Hz, 2H), 3.07-3.03 (m, 2H), 2.87-2.85 (m, 1H), 2.15-2.10
(m, 1H), 1.57-1.54 (m, 1H), 1.52-1.49 (m, 1H), 1.47-1.42 (m, 1H).
1
3
1
C{ H} NMR (150 MHz, CDCl ): δ (ppm) 138.5, 133.9, 50.3, 49.9,
3
47.5, 46.4, 46.3, 37.5, 37.0. HRMS (TOF CI, methane): m/z calcd for
C H13Br : 278.9384 [M+H] ; found: 278.9382. [ꢀ] +8.8 (c = 1.21,
9 2
!
CHCl ).
3
(1R,2R,3R,4S,5R,6R)-2,3-dibromo-5,6-
bis(bromomethyl)bicyclo[2.2.1]heptane (−)−5a: Compound (+)−4
+
!"
(
3.50 g, 12.5 mmol) was dissolved in 155 mL of dry CH
cooled to -78 °C. A solution of Br (0.67 ml, 12.6 mmol) in 110 mL
of dry CH Cl was added dropwise to the reaction mixture over 20
min. The resulting solution was then stirred for 10 min. The reaction
was quenched with aqueous saturated Na and extracted with
CH Cl (3 x 50 mL). Organics were dried with Na SO and concen-
2 2
Cl and
2
i
with hexane: PrOH and monitored by DAD (Diode Array Detector).
Retentions times are quoted in minutes.
Diethyl(1R,2S,3S,4S)-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate
2
2
2 2 3
S O
2
5
(
+)−2: Following the published procedure, compound 2 was ob-
2
2
2
4
1 13
1
tained as a yellow oil (98%, >99% ee) with H NMR and C NMR
trated in vacuo to give 4.70 g of 5a:5b = 12:1 (determined from H
NMR spectrum of the reaction mixture, Figure S25) as a brown oil
1
data in line with the literature. H NMR (500 MHz, CDCl
.27 (dd, 1H, J = 3.3, 5.8 Hz), 6.06 (dd, 1H, J = 2.8, 5.3 Hz), 4.16 (q,
2H, J = 7.5 Hz), 4.06-4.12 (m, 2H), 3.37 (app. t, 1H, J = 4.0 Hz), 3.25
m, 1H), 3.11 (m, 1H), 2.67 (dd, 1H, J = 1.5, 4.5 Hz), 1.61 (d, 1H, J =
3
) δ (ppm):
6
(
85%). The major diastereomer (−)−5a was purified by recrystalliza-
tion from hexanes:CH Cl = 3:1 to give 3.30 g of this compound as a
white solid (60%). m.p. 90-91ºC; (−)−5a: H NMR (600 MHz,
CDCl ): δ (ppm) 4.40 (td, J = 4.1, 1.2 Hz, 1H, H ), 4.02 (dd, J = 4.2,
.8 Hz, 1H, H ), 3.98-3.89 (m, 2H, H and H ), 3.63 (dd, J = 10.2, 5.4
Hz, 1H, H ), 3.26 (dd, app t, J = 9.9 Hz, 1H, H ), 2.88-2.85 (m, 1H,
), 2.70 (s, 1H, H ), 2.22-2.16 (m, 1H, H ), 1.98-1.94 (m, 1H, H ),
.91-1.86 (m, 1H, H ), 1.64-1.60 (m, 1H, H ). C{ H} NMR (150
): δ (ppm) 58.5 (C-2), 56.8 (C-3), 52.3 (C-1), 51.4 (C-5),
2
2
(
1
8
7
1
.5 Hz), 1.43-1.45 (m, 1H), 1.27 (t, 3H, J = 7.5 Hz), 1.23 (t, 3H, J =
.5 Hz). C{ H} NMR (125 MHz, CDCl
37.6, 135.0, 60.8, 60.5, 47.8 (2C), 47.2 (2C), 45.7, 14.2 (2C).
3
f
13 1
3
): δ (ppm) 174.5, 173.3,
2
a
m
l
k
j
Enantioselectivity was determined by GC analysis using a Cyclosil-B
column (110 °C, 25 psi); retention times: 93.2 mins (minor
H
e
b
d
g
13
1
1
c
i
MHz, CDCl
3
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The Journal of Organic Chemistry
Page 8 of 11
5
1.2 (C-6), 49.4 (C-4), 35.4 (C-7), 34.9 (C-endo), 33.9 (C-exo); for
dry round bottom flask. Next, the flask was placed under an atmos-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
additional information, see Figure S1. HRMS (EI): m/z calcd for
C H12Br : 356.8489 [M-Br] ; found: 356.8484. [ꢀ] = −37.4 (c =
9 3
!
phere of nitrogen (after being removed from the glove box) followed
by the addition of dried DMF (1.5 mL) and dimethoxyethane (0.1
mL). After 60 min of stirring at 25 °C, a solution of (−)−(8) (30 mg,
0.06 mmol, 96% ee) was added in dry DMF (0.5 mL) to the mixture
and was stirred at the desired temperature for 12 h. The reaction mix-
ture was cooled to 0 °C and filtered. The filtrate was diluted with
ethyl acetate (1.5 mL), washed with aqueous ammonia (10%, 4 x 0.5
+
!"
1
.06, CHCl
3
).
(
1S,4S)-2-bromo-5,6-dimethylenebicyclo[2.2.1]hept-2-ene 6:
A
solution of a compound (−)−5a (5.00 g, 11.4 mmol) in anhydrous
THF (250 mL) was cooled to 0 °C. Potassium tert-butoxide (9.00 g,
80.2 mmol) was added in portions to the solution. The reaction was
warmed up to room temperature and stirred for 7 h. The reaction was
then cooled to 0 ºC and neutralized with dilute HCl (~1.0 M, 50mL).
mL) and washed with H
with Na SO and concentrated in vacuo. Column chromatography of
the solid residue (SiO , dichloromethane:acetone = from 18:1 to 9:1)
gave compound 10 (11.5 mg, 57%) as a clear oil. H NMR (600 MHz,
CDCl ): δ (ppm) 7.64 (s, 1H), 7.61 (s, 1H), 4.62 (d, J = 1.6 Hz, 1H),
3.91 (d, J = 1.5 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 2.61 (dt, J = 7.8,
2
O (4x1 mL). The organic layer was dried
2
4
Solution was extracted with hexanes (3 x 100mL), dried with Na
2
SO
4
,
2
1
and concentrated in vacuo to obtain 2.20 g of 6 (92%) as a yellow oil;
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R
f
= 0.69 on SiO
2
chromatographic plates with hexanes. H NMR and
3
1
3
42 1
C NMR data from 6 were in line with the literature. H NMR (600
MHz, CDCl ): δ (ppm) 6.20 (d, J = 3.0 Hz, 1H), 5.31 (s, 1H), 5.25 (s,
H), 5.14 (s, 1H), 5.01 (s, 1H), 3.37 (s, 1H), 3.30 (s, 1H), 2.05 (d, J =
1
3
1
1.5 Hz, 1H), 2.28 (dt, J = 7.8, 1.6 Hz, 1H). C{ H} NMR (150 MHz,
CDCl ): δ (ppm) 168.4, 168.3, 152.9, 152.4, 144.4, 131.2, 130.2,
129.7, 123.1, 122.1, 66.3, 59.8, 52.8, 52.7, 52.7. HRMS (ESI-MS):
3
1
8
3
13
1
.3 Hz, 1H), 1.64 (d, J = 8.3 Hz, 1H). C{ H} NMR (150 MHz,
+
CDCl
50.9.
3
): δ (ppm) 146.9, 146.5, 135.4, 127.7 103.4, 102.4, 58.7, 52.2,
m/z calcd for C30
H
24Br
2
O
8
Na: 692.9730 [M+Na] ; found: 692.9726.
!"
[ꢀ] +11.2 (c = 1.50, CHCl ).
3
!
Dimethyl (1S,4S)-2-bromo-1,4-dihydro-1,4-methanonaphthalene-
Hexamethyl(5R,6S,11R,12S,17R,18S)-5,6,11,12,17,18-hexahydro-
5,18:6,11:12,17-trimethanotrinaphthylene-2,3,8,9,14,15-
hexacarboxylate 1syn: Within a glove box, LiNO (7.82 g, 128.3
3
6
,7-dicarboxylate (−)−7: Compound (−)−7 was synthesized from 6
5
1
13
following the literature procedure; H NMR and C NMR spectral
data are consistent with the reported values. H NMR (400 MHz,
1
mmol) was mixed with CuI (18.89 g, 99.2 mmol) inside an oven-dried
flask. Next, the flask was placed under an atmosphere of nitrogen
(after being removed from the glove box) followed by the addition of
dried DMF (340.0 mL) and dimethoxyethane (22.0 mL). After 60 min
of stirring at 25 °C, a solution of compound (−)−8 (6.70 g, 13.4
mmol) was added in dry DMF (110.0 mL) to the mixture and was
stirred at the desired temperature for 12 h; the reaction time could be
shorten if, desired, with the same outcome (Figure 3F). The filtrate
was diluted with ethyl acetate (350.0 mL), washed with aqueous am-
CDCl
3
): δ (ppm) 7.65 ppm (1H, s), 7.51 (1H, s), 6.73 (d, J = 3.2 Hz,
1
2
1
6
H), 4.00 (1H, s), 3.88 (6H, s), 3.85 (1H, s), 2.63 (d, J = 8.0 Hz, 1H),
1
3
1
.35 (d, J = 7.6 Hz, 1H). C{ H} NMR (100 MHz, CDCl
3
): δ (ppm)
68.4, 168.1 , 153.9, 153.3, 139.8, 135.8, 130.1, 128.9, 122.1, 121.5,
!"
3
8.8, 58.2, 52.7, 52.6, 51.7. [ꢀ]! = −48.8 (c = 0.98, CHCl ). Enanti-
opurity of (−)−7 was determined to be 98% ee by HPLC analysis
Figures S3 and S4) using an AD-H column (hexanes:isopropanol =
(
96:4, 1 mL/min); retention times: 15.6 min (+)−7 and 19.4 min (−)−7.
Dimethyl (1S,4R)-2-bromo-3-(trimethylstannyl)-1,4-dihydro-1,4-
methanonaphthalene-6,7-dicarboxylate (−)−8: Compound (−)−8
was synthesized from (−)−7 following an already published proce-
monia (10%, 4 x 100 mL) and washed with H
organic layer was dried with Na SO and then concentrated in vacuo
to give a solid residue subjected to column chromatography (SiO
CH Cl :acetone = from 18:1 to 9:1) yielded 1.48 g of 1 (43%) and
2
O (4 x 60 mL). The
2
4
2
,
43
1
13
2
2
syn
dure; H NMR and C NMR spectral data are consistent with the
1
13
1
1.44 g of 1anti (42%) as white solids. H NMR and C NMR data
corresponding to compounds 1syn were in line with the literature.
reported values. H NMR (400 MHz, CDCl
3
): δ (ppm) 7.65 (s, 1H),
43 1
H
7.47 (s, 1H), 4.09 (s, 1H), 3.91 (s, 7H), 2.57 (d, J = 7.6 Hz, 1H), 2.27
1
3
1
NMR (400 MHz, CDCl ): δ (ppm) = 2.54 (s, 6H), 3.80 (s, 18H), 4.43
3
(
d, J = 7.6 Hz, 1H) and 0.24 (s, 9H). C{ H} NMR (100 MHz,
CDCl ): δ (ppm) 168.5, 168.4, 154.0, 153.6, 152.2, 147.0, 129.0,
22.0, 121.1, 68.4, 60.2, 57.0, 52.6, 52.5, -9.3. [ꢀ] !! " = −33.1 (c =
.18, CHCl ). Enantiopurity of (−)−8 was determined to be 96% ee by
13
1
(
s, 6H), and 7.45 (s, 6H). C{ H} NMR (100 MHz, CDCl
167.7, 152.6, 137.6, 129.3, 121.2, 65.0, 51.8, 48.5.
Cyclotrimerization of (−)−8 in the presence of (+)−10: Within a
glove box, LiNO (35 mg, 0.51 mmol) was added to CuI (85 mg, 0.45
3
) δ (ppm) =
3
1
1
3
3
HPLC analysis (Figures S5 and S6) using an AD-H column
(hexanes:iosopropanol = 96:4, 1 mL/min); retention times: 6.5 min for
mmol) inside an oven-dried flask. The flask was placed under an
atmosphere of nitrogen (after being removed from the glove box)
followed by the addition of dry DMF (1.5 mL) and dimethoxyethane
(0.1 mL). After 60 min of stirring at 25 °C, a solution of (−)−8 (30
mg, 0.06 mmol) and (+)−10 (13 mg, 0.02 mmol) in dry DMF (0.5
mL) was added to the mixture and stirred for 12 h. The reaction mix-
ture was cooled to 0 °C and filtered. The filtrate was diluted with
ethyl acetate (1.5 mL), washed with aqueous ammonia (10%, 4 x 0.5
(
+)−8 and 8.6 min for (−)−8.
Dimethyl (1S,4S)-2-iodo-1,4-dihydro-1,4-methanonaphthalene-
,7-dicarboxylate (−)−9: Dry copper (I) iodide (0.20 g, 1.1 mmol)
6
and NaI (2.00 g, 13.3 mmol) were added to a round bottom flask. A
solution of (−)−(7) (0.50 g, 1.5 mmol) in 3 mL of 1,4-dioxane along
with N,N′-dimethylethylenediamine (0.1 mL, 0.9 mmol) were added
to the same flask. The suspension was heated to reflux for 10 h under
an atmosphere of nitrogen. The reaction mixture was then cooled to
mL) and washed with H
with Na SO and concentrated in vacuo. Column chromatography of
the solid residue (SiO , dichloromethane:acetone = from 18:1 to 9:1)
2
O (4 x 1 mL). The organic layer was dried
2
4
ambient temperature, diluted with CH
0% NH OH (aq). Organic layer was dried with Na
trated in vacuo. The resulting brown-black oil was filtered through a
silica plug (CH Cl :EtOAc = 3:1) to, after the solvent removal, give
.52 g of 9 as a yellow oil (91%); R = 0.39 on SiO chromatographic
plates with hexanes:EtOAc = 4:1. H NMR (850 MHz, CDCl ): δ
ppm) 7.66 (s, 1H), 7.51 (s, 1H), 7.06 (d, J = 3.2 Hz, 1H), 3.97 (m,
1H), 3.95 (m, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 2.59 (d, J = 7.7 Hz, 1H),
2
Cl
2
(20 mL) and washed with
2
3
4
2
SO and concen-
4
gave 1syn (4.7 mg), 1anti (5.5 mg) and (+)−10 (11.3 mg) as white sol-
ids.
2
2
Compound
(−)−7
from
mixture
of
(−)−5a
and
0
f
1
2
(1R,2S,3S,4S,5R,6R)-2,3-dibromo-5,6-
3
bis(bromomethyl)bicyclo[2.2.1]heptane 5b.
A solution of
(
(
−)−5a:5b = 12:1 (0.25 g, 0.57 mmol) in anhydrous THF (15 mL),
1
3
1
and under an atmosphere of nitrogen, was cooled to 0 °C. To this
solution, potassium tert-butoxide (0.440 g, 3.92 mmol) was added in
portions. The reaction mixture was allowed to warm to room tempera-
ture and stirred for 7 h. The reaction was then cooled to 0 °C and
neutralized with dilute HCl (15 mL, 1M). Solution was extracted with
2.25 (d, J = 7.6 Hz, 1H). C{ H} NMR (214 MHz, CDCl
3
): δ (ppm)
68.7, 168.3, 153.7, 153.5, 148.8, 130.2, 129.0, 122.3, 121.8, 105.3,
9.2, 61.4, 53.0, 52.8, 52.7. HRMS (EI): m/z calcd for C15 Na:
06.9751 [M+Na] ; found: 406.9746. [ꢀ] = −50.6 (c = 1.54,
1
6
4
H
13IO
4
+
!"
!
3
CHCl ). Enantiopurity of (−)−9 was determined to be 98% ee by
HPLC analysis (Figures S7 and S8) using an AD-H column
(hexanes:isopropanol = 96:4, 1 mL/min); retention times: 15.9 min for
hexanes (3 x 10 mL), dried with Na
low temperature to give 0.10 g of 6 as yellow oil. To a solution of 6
0.10 g, 0.52 mmol) in dry toluene (3 mL), dimethyl acetylenedicar-
2 4
SO , and concentrated in vacuo at
(
(
+)−9 and 20.2 min for (−)−9.
boxylate (0.1 mL, 0.82 mmol) was added. The solution was brought
to reflux and stirred overnight. The reaction was then concentrated in
vacuo to give 0.18 g of the cycloaddition product as a yellow oil. To a
Bis-3,3’-(dimethyl(1S,4S)-2-bromo-1,4-dihydro-1,4-
methanonaphthalene-6,7-dicarboxylate) (+)−10: Copper(II)triflate
65 mg, 0.18 mmol) and LiNO (12 mg, 17 mmol) were added to a
(
3
ACS Paragon Plus Environment

Page 9 of 11
The Journal of Organic Chemistry
solution of (0.18g, 0.52 mmol) of the cycloaddition adduct in CH
(8 mL), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was
added (0.270 g, 1.19 mmol). The solution was stirred overnight at
room temperature, then filtered to remove excess of DDQ, washed
2
Cl
2
Additional synthetic, X-ray crystallography (cif file), spectroscop-
ic and computational details. The Supporting Information is avail-
able free of charge on the ACS Publications website.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with aq. NaHCO
with aq. NaHCO
solvent removed under reduced pressure. Column chromatography
3
and filtered again. Next, the solution was extracted
AUTHOR INFORMATION
Corresponding Author
3
, the organic layer dried with Na SO and the
2
4
(
SiO
2
) with hexanes:ethyl acetate = from 15:1 to 3:1, gave 0.14 g of
*
badjic.1@osu.edu
(
−)−7 as a viscous yellow oil (75% over 3 steps). R
f
= 0.39 on SiO
2
1
13
chromatographic plates with hexanes:ethyl acetate = 4:1. H/ NMR
spectroscopic data was in agreement with those reported above.
Enantiopurity of (−)−(7) was determined to be 84 % ee by HPLC
analysis (Figure S11) using an AD-H column (hexanes:isopropanol =
96:4, 1 mL/min); retention times: 15.6 min for (+)−(7) and 19.4 min
for (−)−(7).
ACKNOWLEDGMENT
This work was financially supported with funds obtained from the
National Science Foundation under CHE-1606404 to J.D.B. and
under CHE-1566106 to C.M.H. Generous computational re-
sources were provided by the Ohio Supercomputer Center. We
thank Prof. Christo Sevov (OSU) for inspiring discussions.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Compound (−)−8 from (−)−5a/5b mixture: Compound 8 was
5
synthesized following the same literature procedure as enantiopure
1
13
8
; H NMR and C NMR spectral data are consistent with the report-
REFERENCES
1
13
ed values. H/ NMR spectroscopic data was in agreement with those
reported above. Enantiopurity of (−)−(8) was determined to be 84 %
ee by HPLC analysis (Figures S12) using an AD-H column
1
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(
(
hexanes:iosopropanol = 96:4, 1 mL/min); retention times: 6.5 min for
+)−(8) and 8.6 min for (−)−(8).
Compound 1syn from (−)−5a/5b mixture: Within a glove box,
LiNO (5.60 g, 91.9 mmol) was mixed with CuI (13.60 g, 71.4 mmol)
3
inside an oven-dried flask. Next, the flask was placed under an at-
mosphere of nitrogen (after being removed from the glove box) fol-
lowed by the addition of dried DMF (240 mL) and dimethoxyethane
(
(
16 mL). After 60 min of stirring at 25 °C, a solution of compound
−)−8 (4.80 g, 9.6 mmol; 84% ee) was added in dry DMF (80 mL) to
the mixture and was stirred at the desired temperature for 12 h. The
filtrate was diluted with ethyl acetate (250 mL), washed with aqueous
ammonia (10%, 4 x 75 mL) and washed with H
organic layer was dried with Na SO and then concentrated in vacuo
to give a solid residue subjected to column chromatography (SiO
CH Cl :acetone = from 18:1 to 9:1) yielded 0.91 g of 1syn (37 %) and
1.18 g 1anti (48 %) as white solids. H NMR and C NMR data corre-
2
O (4 x 50 mL). The
2
4
2
,
2
2
1
13
4
3
sponding to compound 1syn were in line with the literature.
1
13
H/ NMR spectroscopic data was in agreement with those reported
above.
Dimethyl(1S,4S)-2-chloro-1,4-dihydro-1,4-methanonaphthalene-
6,7-dicarboxylate (−)−16: Dry copper (I) iodide (0.20 g, 1.1 mmol)
and tetramethyl ammonium chloride (1.50 g, 13.7 mmol) was added
to a round bottom flask. A solution of compound (−)−7 (0.50 g, 1.5
Badjic, J. D.,
A Stimuli-Responsive Molecular Capsule with
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in
1,4-dioxane
(3
mL)
along
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dimethylethylenediamine (0.1 mL, 0.9 mmol) were added to the same
flask. The suspension was heated to reflux for 10 h under an atmos-
phere of nitrogen. The reaction mixture was cooled down, diluted
with CH
layer was dried with Na
brown-black oil was filtered through a silica plug (CH
:1) to, after the solvent removal, give 0.36 g of (−)−16 as a yellow
oil (82%); 0.39 on SiO chromatographic plates with
hexanes:EtOAc = 4:1. H NMR (850 MHz, CDCl ): δ (ppm) 7.66 (s,
H), 7.52 (s, 1H), 6.47 (d, J = 3.2 Hz, 1H), 3.99-3.98 (m, 1H), 3.88 (s,
H), 3.88 (s, 3H), 3.79-3.77 (m, 1H), 2.62 (d, J = 7.6 Hz, 1H), 2.34
2
Cl
2
(20 mL) and washed with 30% NH
SO and concentrated in vacuo. The resulting
Cl :EtOAc =
4
OH (aq). Organic
2
4
2
2
3
R
f
=
2
1
9
. Chen, S.; Wang, L.; Polen, S. M.; Badjic, J. D., Gating the
3
Trafficking of Molecules across Vesicular Membrane Composed of
Dual-Cavity Baskets. Chem. Mater. 2016, 28, 8128-8131.
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3
13
1
1
0. Cavaliere, V. N.; Mindiola, D. J., Methane: a new frontier in
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1. Alsbaiee, A.; Smith, B. J.; Xiao, L.; Ling, Y.; Helbling, D. E.;
(
1
d, J = 7.6 Hz, 1H). C{ H} NMR (214 MHz, CDCl
68.6, 168.3, 154.4, 153.4, 148.3, 135.2, 130.2, 129.1, 122.3, 121.7,
68.7, 56.7, 52.7, 52.7, 50.7. HRMS (ESI-MS): m/z calcd for
3
): δ (ppm)
1
+
!"
Dichtel, W. R., Rapid removal of organic micropollutants from water
by a porous β-cyclodextrin polymer. Nature 2016, 529, 190-194.
C
=
15
H
13ClO
4
Na: 315.0395 [M+Na] ; found: 315.0388. [ꢀ]! = −43.8 (c
1.17, CHCl ). Enantiopurity of (−)−(16) was determined to be 98%
3
1
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hexanes:isopropanol = 96:4, 1 mL/min); retention times: 14.7 min for
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+)−16 and 18.0 min for (−)−16.
1
4. Fabris, F.; Zonta, C.; Borsato, G.; De Lucchi, O.,
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3
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3
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1
2
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4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
31.
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0. (a) Allred, G. D.; Liebeskind, L. S., Copper-Mediated Cross-
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