Preparation of enediyne-crosslinked networks and their reactivity under thermal and mechanical conditions

Article abstract of DOI:10.1016/j.tet.2008.04.106

The COGEF technique (COnstrained Geometries simulating External Force) was used to investigate the effects of macroscopic forces on cyclic enediynes, which can undergo Bergman Cyclization (BC). Because the forces needed to activate BC were found to be less than the forces needed for chain scission in?polymer backbones, the calculations suggest that enediynes are potentially useful mechanophores. Three enediynes studied computationally were synthesized. The thermal BC reactions for these compounds were studied by DSC and found to be consistent with the predicted thermal sensitivity based on known substituent effects. However, upon incorporation of the enediynes into a polymer matrix as crosslinks, no definitive mechanical activation was observed, and conclusions about the stress-sensitivity of enediynes were unable to be drawn. Model studies suggest that insufficient force was applied to the crosslinks for mechanical activation to be observable by DSC.

Full text of DOI:10.1016/j.tet.2008.04.106

Tetrahedron 64 (2008) 8435–8448
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation of enediyne-crosslinked networks and their reactivity under thermal
and mechanical conditions
,
,
,b,
Charles R. Hickenboth a b, Joseph D. Rule a b, Jeffrey S. Moore a
*
a Department of Chemistry, The University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
b The Beckman Institute for Advanced Science and Technology, The University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The COGEF technique (COnstrained Geometries simulating External Force) was used to investigate the
effects of macroscopic forces on cyclic enediynes, which can undergo Bergman Cyclization (BC). Because
the forces needed to activate BC were found to be less than the forces needed for chain scission
in polymer backbones, the calculations suggest that enediynes are potentially useful mechanophores.
Three enediynes studied computationally were synthesized. The thermal BC reactions for these com-
pounds were studied by DSC and found to be consistent with the predicted thermal sensitivity based on
known substituent effects. However, upon incorporation of the enediynes into a polymer matrix as
crosslinks, no definitive mechanical activation was observed, and conclusions about the stress-sensitivity
of enediynes were unable to be drawn. Model studies suggest that insufficient force was applied to the
crosslinks for mechanical activation to be observable by DSC.
Received 26 January 2008
Received in revised form 9 April 2008
Accepted 25 April 2008
Available online 30 April 2008
This paper is dedicated to Professor Fraser
Stoddart for the inspiration that he has
provided throughout the years
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
rate of BC can be accelerated by mechanical tensile forces applied
in such a manner that decrease d. Here we report the design,
Interest in the use of mechanical energy to alter the reactivity of
polymers containing stress-sensitive mechanophores has been in-
creasing as of late.1–17 It has been shown that mechanical forces not
only can modify the rate of chemical reactions, but also can modify
the outcome of the reaction to yield products not typically observed
by thermo- or photochemistry. However, chemical reactions that
are influenced by mechanical forces remain poorly understood, and
there is a need for the discovery of new mechanophores.
computational optimization, and synthesis of cyclic enediyne
crosslinkers. We also begin to address experimental protocols for
accessing the study of stress-accelerated reactions in the solid state.
2. Results and discussion
Because uniaxial tension causes elongational deformations
along the vector of its application, it was hypothesized that
There has been great interest in the scientific community in
controlling the reactivity of the enediynes, which undergo Bergman
cyclization (BC),18 a cycloaromatization rearrangement to a 1,4-
benzyne diradical intermediate.19 Strategies have been devised to
trigger cycloaromatization on demand through physical stimuli
such as heat, light,20 or electrical potential,21 or various chemical
stimuli such as transition metal coordination22,23 or chemical
modification. However, to the best of our knowledge, triggering BC
with external mechanical forces has never been reported.
There is significant literature precedent that enediynes are
sensitive to molecular deformations.24–30 Specifically, it has been
suggested that when the acetylene distance d is less than 2.9–3.4 Å,
enediynes undergo spontaneous cyclization at ambient tempera-
tures.31,32 With this precedent in mind, we hypothesized that the
10
OH
8
d
6
4
OH
3
2
0
OH
-2
-4
d
OH
HO
-6
2
d
HO
-8
1
-10
0
2
4
% Backbone Elongation =
6
8
10
12
/
Figure 1. Plot of change in distance d versus percent backbone elongation. To produce
these curves, the backbone length [ was systematically elongated in enediynes 1, 2, and
3, and the geometry was minimized at the molecular force field level at each step.
* Corresponding author.
E-mail address: moore@scs.uiuc.edu (J.S. Moore).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.106

8436
C.R. Hickenboth et al. / Tetrahedron 64 (2008) 8435–8448
8
OH
11
8
OH
11
7
9
8
1
4
11
7
1
4
7
9
1
4
2
3
2
3
6
2
3
OH
6
6
14
14
14
13
13
HO
13
HO
5
5
5
12
12
12
10
9
10
OH
10
1
2
3
(a)
(b)
(c)
1
ΔΘ = -4.7°
ΔΘ = -4.1°
ΔΘ = -1.8°
1
2
3
ΔΘ = -7.1°
ΔΘ = -4.5°
ΔΘ = -3.2°
1
2
3
ΔΘ = -0.3°
ΔΘ = 2.1°
ΔΘ = 4.0°
2
3
(d)
(e)
(f)
1
2
3
ΔΘ = -0.1°
ΔΘ = 2.6°
ΔΘ = -1.8°
1
2
3
ΔΘ = 1.3°
ΔΘ = 4.3°
ΔΘ = 3.1°
1
2
3
ΔΘ = 4.5°
ΔΘ = 1.3°
ΔΘ = 4.0°
Figure 2. Analysis of bond angle distortions with applied stress for enediynes 1, 2, and 3. Dq is defined as the difference in the bond angles between the ground state and after 10%
backbone elongation. Negative values imply that the angle is decreasing in value.
connection of the polymer backbone to different points on a cyclic
enediyne would result in varying levels of efficiency in decreasing
distance d, and therefore varying levels of stress activation. This
idea was investigated computationally using the COGEF computa-
tional technique.33 The distance between the hydroxyl-containing
carbons of cyclic enediynes 1, 2, and 3 were fixed and all other
atoms were allowed to fully relax. By systematically increasing the
fixed distance and monitoring distance d at each interval, a profile
of percent change in d versus percent backbone elongation was
created (Fig. 1). In the first 10% elongation of enediyne 1, there is
approximately an 8% decrease in d. Furthermore an acetylene dis-
tance of 3.2 Å is reached after a 9% increase in backbone length. The
major molecular distortions responsible for the decrease in d are
the bending of the 2–3–9 and 3–9–10 bonds in skeleton 4 (Fig. 2).
For this isomer, very little strain is manifested in bond stretching,
which is unproductive at decreasing distance d (Fig. 3). In contrast,
8
7
OH
11
8
OH
11
8
1
4
11
7
1
4
7
9
1
4
2
3
2
3
6
2
3
OH
6
6
14
14
14
13
13
HO
13
HO
5
5
5
12
12
12
9
10
9
10
10 OH
1
2
3
(a)
(b)
(c)
1
2
3
Δ x = 0.02 Å
Δ x = 0.01 Å
Δ x = 0.02 Å
1
2
3
Δ x = 0.01 Å
Δ x = 0.01 Å
Δ x = 0.01 Å
1
Δ x = 0.03 Å
Δ x = 0.01 Å
Δ x = 0.04 Å
2
3
(d)
(e)
(f)
1
Δ x = 0.04 Å
Δ x = 0.11 Å
Δ x = 0.02 Å
1
Δ x = 0.02 Å
Δ x = 0.04 Å
Δ x = 0.01 Å
1
Δ x = 0.05 Å
Δ x = 0.19 Å
Δ x = 0.08 Å
2
2
2
3
3
3
Figure 3. Analysis of bond stretching distortions with applied stress for enediynes 1, 2, and 3.
Dx is measured as the difference in bond length in the ground state and after 10%
backbone elongation.

C.R. Hickenboth et al. / Tetrahedron 64 (2008) 8435–8448
8437
enediyne 2 does not effectively couple the backbone tensile de-
formation with the desired decrease in d. Less than a 1% decrease in
d occurs after 10% elongation. Because the geometry is not opti-
mized to bend bonds, much of the stress is stored internally
through bond stretching deformations, particularly the 2–7 and 8–
11 single bonds (Fig. 3). At higher levels of elongation (greater than
13%) distance d reaches a minimum value and begins to increase.
Application of force to isomer 3 increases d, consistent with in-
tuitive expectations. Thus, cycloaromatization for this isomer is
predicted to be inhibited by tensile force. From this series of cal-
culations it is predicted that the BC of enediyne 1 will be promoted
by tensile force, that of enediyne 2 will be unaffected by tensile
force, and that of enediyne 3 will be inhibited by tensile force. This
set of isomers can potentially be used to test the idea that the ge-
ometry of the mechanophore plays a role in stress activation.
A plot of
D
E versus (
D
[)2 is then expected to be linear with
a slope of k0/2. Modeling the deformation in this way yields a plot of
D
E versus (D
[)2, which is approximately linear at small distortions
(less than 2.0 Å) but becomes non-linear at higher elongations
(Fig. 6); the sum of bond deformations acts as an ideal spring only at
small deformations. Under this approximation, the spring constant
k0 was estimated to be 36.8 N/m.
Figure 1 shows that
D[ is proportional to Dd,
D
d ¼ k [;
D
(4)
and the slope of that plot shows that the value of k is 0.83. Com-
bining Eq. 4 with Eq. 1, rearranging, and using the numerical values
of k0 and k give:
OH
OH
OH
HO
HO
OH
1
2
3
4
The above calculations reveal, which substitution pattern is the
most efficient at coupling the decrease in d with elongational
forces. However, if the mechanochemical process is to precede
polymer chain scission, the applied forces must induce the neces-
sary molecular distortions before rupturing chemical bonds in the
polymer backbone (Fig. 4). To investigate whether this condition is
met, a profile of relative energy as a function of molecular elon-
gation was produced using quantum mechanical calculations at the
D
d ¼ ꢀ2:26 ꢁ 10ꢀ2F
(5)
which is approximately valid when F is less than 8.8 nN. With this
equation, it is possible to estimate to what extent d will be reduced
by a given force, and, therefore, if cycloaromatization will be
125
DFT B3LYP/6-31G level. To create this profile, distance [ was sys-
*
tematically increased (Fig. 5) with a corresponding decrease in
acetylene distance d. At each step the change in energy relative to
the undistorted ground state was calculated. Assuming that the
OH
100
HO
sum of all bond distortions acts as a spring,
D[ is related to the force
1
75
(F) and work (W) through Eqs. 1 and 2:
F ¼ ꢀk0
D
[
(1)
(2)
50
25
0
W ¼ ꢀk0ð
D
[Þ2
Furthermore, by assuming that the work done on the molecule
by stress is approximated by the relative energy difference
between the stressed state and the undistorted ground state
0
1
2
3
(D
E¼Estressed stateꢀEground state), Eq. 2 can be rewritten as Eq. 3:
(Å)
E ¼ ꢀk0ð
D
[Þ2
(3)
Figure 5. Plot of change in ground state energy versus
6-31G level.
D[ calculated at the DFT B3LYP/
D
*
O
O
F < FC-C
d
Mechanical Activation Pathway
O
O
F > FC-C
d
O
O
Chain Scission Pathway
Figure 4. The two competing mechanochemical pathways. If the force required to activate the linker is less than that required to cleave C–C bonds in the polymer backbone, the
mechanical activation pathway will preempt chain scission. If the force required to activate the linker is too large, the chain scission pathway will dominate.

8438
C.R. Hickenboth et al. / Tetrahedron 64 (2008) 8435–8448
90
75
60
45
30
15
0
group was then protected as the tetrahydropyran acetal upon
treatment with 3,4-dihydropyran and a catalytic amount of pTSA
monohydrate to yield iodide 5 (Scheme 1).
Enediyne linker 1 was prepared according to Scheme 1. Iodide 5
was coupled with triisopropylsilylacetylene under palladium-cat-
alyzed cross-coupling conditions to yield alkyne 6. Enediyne 7 was
prepared by coupling alkyne
6 with trimethylsilylacetylene,
employing the highly active Pd(PtBu3)2 catalyst.35 Less reactive
palladium catalysts such as Pd(PPh3)4 and PdCl2(PPh3)2 gave poor
yields of the enediyne product. The trimethylsilyl group was se-
lectively removed with aqueous lithium hydroxide,36 then terminal
acetylene 8 was deprotonated with nBuLi and treated with 1-[2-
(tert-butyldimethylsilyl)oxy]-ethyloxirane to provide alcohol 9.
Protection of the hydroxyl group as the tetrahydropyran acetal and
deprotection with TBAF yielded enediyne 10. The primary alcohol
was converted to iodide 11, which set up ring closing through nu-
cleophilic displacement.37 Treatment of iodide 11 with LDA in the
presence of HMPA effected ring closure, then cleavage of the acetal
protecting group with pTSA and methanol yielded linker 1.
y = 18.443x - 1.9903
R2 = 0.9936
0
2
4
2 (m2 X 10-20
6
8
)
Figure 6. Plot of relative energy versus (D
[)2 for enediyne 1. Only the linear region (red
squares) was used in the calculation of the spring constant; the non-linear region
(green triangles), presumably influenced by the proximity of the transition state, was
neglected.
To prepare propargylic enediyne 2, iodide 5 was coupled with 5-
hexyn-1-ol under palladium-catalyzed cross-coupling conditions,
to yield bromide 13a and iodide 13b as a 47:3 mixture by 1H NMR
(Scheme 2). This mixture was carried through without separation,
and was coupled with trimethylsilylacetylene in the presence of
activated before polymer scission occurs. It takes approximately 5–
6 nN of force per chain to overcome the binding potential of a C–C
bond in poly(ethylene glycol). This value can be used as an ap-
proximation of the maximum force accessible to distort an ene-
diyne linker. From Eq. 5, a force of 5 nN is predicted to cause a 1.3 Å
deformation. This is large enough to decrease distance d below the
3.2–3.0 Å range required for spontaneous cyclization. The estimates
made above fail to account for any change in the transition state
energy as a result of the applied external force.
In order to empirically test the above models, enediynes 1, 2,
and 3 were prepared. The synthesis of enediynes 1 and 2 began
with 4-bromo-3-iodoanisole.34 The methyl ether was cleaved with
boron trifluoride–dimethyl sulfide complex, and the hydroxyl
36
Pd(PtBu3)2 and zinc bromide. The trimethylsilyl group was re-
moved with TBAF to provide terminal alkyne 14, which was treated
with 2 equiv of LDA, followed by 1 equiv of iodine, to yield
iodoalkyne 15. Oxidation of the alcohol to the aldehyde with pyr-
idinium dichromate then provided the appropriate functionality for
ring closure. Treatment of aldehyde 16 with chromium chloride and
nickel chloride yielded the ring closed product,38 which was
deprotected under acidic conditions to provide propargylic linker 2.
Bispropargyl enediyne 3 was prepared starting from 1-(triiso-
propylsilylethynyl)-2-ethynylbenzene 17 (Scheme 3).39 The lithium
acetylide of this enediyne, obtained upon treatment of enediyne 17
Br
Br
1) BF3SMe2, CH2Cl2
2) 3,4-dihydropyran,
pTSA, CH2Cl2, 73%
H3CO
H
I
THPO
I
5
Br
i
Si(Pr)3
H
Si(CH3)3
5
t
PdCl2(PPh3)2, CuI,
TEA, Ar, 93%
Pd(P Bu3)2, ZnBr2,
DIA, DMF, Ar, 94%
THPO
i
6
Si(Pr)3
O
Si(CH3)3
H
OTBS
1 M LiOH
MeOH/THF, 95%
1) nBuLi, THF, -78 °C
2) BF3OEt2 , 77%
THPO
THPO
THPO
i
i
7
Si(Pr)3
8
Si(Pr)3
OTHP
OH
PPh3, I2, imidazole
68%
1) 3,4-dihydropyran, pTSA
2) TBAF, THF, 89%
THPO
OH
OTBS
i
H
Si(Pr)3
10
9
OTHP
1) nBuLi, THF/HMPA, -78 °C
2) pTSA, MeOH/THF, 29%
OH
THPO
I
HO
( )
H
1
11
Scheme 1. Preparation of enediyne linker 1.

C.R. Hickenboth et al. / Tetrahedron 64 (2008) 8435–8448
8439
4OH
Br
5-hexyn-1-ol
H
Si(CH3)3
+
5
t
PdCl2(PPh3)2, CuI
TEA, Ar, 86% (47:3 a:b)
1) Pd( Bu3)2, ZnBr2,
THPO
H
THPO
I
OH
DIA,DMF, Ar
13a
13b
2) TBAF, THF, 74%
4
I
1) LDA, THF
2) I2, 86%
PDC
CH2Cl2, 82%
THPO
THPO
OH
4
14
15
OH
3
I
OH
1) CrCl2, NiCl2, THF
2) AcOH/THF, 41%
H
THPO
HO
O
( ) 2
16
3
Scheme 2. Preparation of propargylic enediyne 2.
with nBuLi, was reacted with 4-[(tert-butyldimethylsilyl)oxy]-
butanal to yield enediyne 18. The newly formed hydroxyl group
was protected as the tetrahydropyran acetal, and then the silyl
groups were cleaved with TBAF to yield enediyne 19. Next, the
terminal acetylene was converted to the iodoacetylene by treat-
ment with LDA and iodine as described above. The hydroxyl group
was then oxidized with pyridinium dichromate to aldehyde 20, and
the ring was closed by treatment with chromium chloride and
nickel chloride.38 The tetrahydropyran protecting group was then
cleaved to yield cyclic enediyne 3.
temperatures for cycloaromatization were being masked. To cir-
cumvent this problem, the diols were protected as diacetates, and
the diacetates were analyzed by DSC as solutions in 1,3-dime-
thoxybenzene. This solvent was chosen both for its high boiling
point and for solubility considerations. The strategy was successful
at eliminating the melting reactions. DSC analysis then confirmed
the predicted order (Fig. 7). The onset reaction temperature was
found to be 105, 113, and 123 ꢂC for the bispropargyl diacetate 23,
propargyl acetate 22, and homopropargyl acetate 21, respectively.
Previous studies have shown that the radicals produced by BC
successfully initiate the polymerization of unsaturated mono-
mers;42,43 it was hypothesized that this characteristic could be used
as a probe to detect small amounts of cyclization that might be
occurring under mechanical forces. More specifically, it was hy-
pothesized that under stress activation the exotherm of polymeri-
zation initiated by cycloaromatization would shift to lower
temperatures, which would be detectable by DSC. The enediynes
must be incorporated into polymers for mechanochemical activa-
tion because small molecules are relatively inert to macroscopic
stress. Furthermore, since monomer must be present during the
experiment, the polymer must be a crosslinked network to prevent
dissolution of the polymer in the monomer, which would make
stress application difficult within a DSC instrument. Therefore, it
was concluded that the best approach was to incorporate the
enediynes as crosslinks into a PMMA network. The material would
It has been shown that s-electron withdrawing groups and p-
electron donating groups at the termini of the acetylenic positions
of enediynes lower the barrier for cycloaromatization.40 Thus it was
anticipated that the order of thermal reactivity of the diols would
be bispropargyl 3>propargyl 2>homopropargyl 1. A DSC study was
undertaken to confirm this expected order, since it has been shown
to be a convenient method for the study of cycloaromatization.41
Because the polymerization of the radicals produced by BC is exo-
thermic, there is no need for external trapping reagents and the
enediynes can be analyzed neat. However, it was found that neat
analysis of the diols by DSC was complicated by the fact that the
onset temperature of reaction was dependant on the melting point
of the diol. In other words, the enediynes needed to melt before
undergoing cyclization, and the melting point of the crystals was
above the onset temperature for BC. Therefore, the true onset
OH
O
H
OTBS
1) 3,4-dihydropyran, CH2Cl2
OTBS
H
2) TBAF, THF, 72%
nBuLi, THF, 95%
i
i
SiPr3
SiPr3
18
17
OTHP
OTHP
OH
OH
1) NiCl2,CrCl2, THF
1) LDA, I2, THF
H
2) pTSA, MeOH/THF, 39%
2) PDC, CH2Cl2, 63%
OH
O
I
H
3
20
19
Scheme 3. Preparation of bispropargylic enediyne 3.

8440
C.R. Hickenboth et al. / Tetrahedron 64 (2008) 8435–8448
1.4
1
then be swollen with monomer. Swelling would simultaneously
apply stress to the crosslinks and provide the monomer for poly-
merization (Fig. 8).
OAc
AcO
The general stress levels that can be produced through swelling
of these polymer networks can be estimated through both theo-
retical approximations and experimental measurements of related
systems. The PMMA networks in these experiments have 0.17 mol %
crosslinker corresponding to an average of about 600 C–C bonds (n)
between crosslinks. Assuming a characteristic ratio (CN) of 8.6544
and a bond length (l) of 1.54 angstroms, the root mean square
distance between these crosslinks would be approximately 11.1 nm
22
OAc
OAc
AcO
21
0.6
0.2
OAc
23
(CR20D1/2¼(nl2CN
)
1/2). The average contour length of the chains be-
tween crosslinks would be about 75 nm. Therefore, upon swelling,
it is reasonable to assume that the distance between crosslinks may
increase by as much as tens of nanometers.
-0.2
The force due to entropy along a single chain section between
50
100
150
Temperature (C)
200
250
crosslinks as it is elongated can be estimated by Eq. 6:45
Figure 7. DSC analysis of bisacetates 21, 22, and 23. The onset temperatures for BC
were found to be 123, 113, and 105 ꢂC, respectively. In this DSC scan, exothermic is
positive heat flow (larger positive heat flow¼more exothermic). All scans were found
to be irreversible.
f ¼ ð3kbTÞ=ð2lpLÞ
d
(6)
where kb is Boltzman’s constant, T is the temperature, lp is the
persistence length, L is the contour length, and is the extension
d
length. The persistence length of PMMA has been reported to be
0.72 nm;44 this corresponds to forces in the range of 10ꢀ13–10ꢀ12 N
as the network swells to levels less than twice its original size. This
agrees reasonably well with experimentally observed forces due to
polystyrene chains elongated to moderate levels (i.e., significantly
less than the contour length).45
MMA
Swelling
From Eq. 5, it is expected that a force of 1 pN would not decrease
distance d significantly, and would likely be insufficient to produce
rapid BC at ambient temperatures. However, because the predicted
force due to swelling is only an average value in a polydisperse
system, there will be a fraction of crosslinks bearing higher forces.
In addition, by testing the samples under a temperature ramp, it
seemed possible that the expected forces due to swelling may be
enough to slightly lower the temperature at which radical forma-
tion is first detected in the system. In order to increase the peak
stress on those crosslinkers bearing the bulk of the load, the low
crosslinker level of 0.17 mol % was chosen.
To test this hypothesis, enediyne 1 was functionalized such that
it could be incorporated as a crosslinker into a polymeric material.
Bismethacrylate 24 was prepared by treatment of diol 1 with
methacroyl chloride (Scheme 4). This enediyne crosslinker was
incorporated into poly(methyl methacrylate) microspheres at
0.17 mol % relative to monomer by suspension polymerization of
methyl methacrylate in water using a room temperature benzoyl
peroxide/N,N-dimethylaniline initiation system.46
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Figure 8. The bulk material test for stress reactivity. The mechanochemical linker is
functionalized as a bismethacrylate and polymerized as a crosslinker in PMMA beads.
The beads are then swollen with monomer, and tension forces build on the crosslinks.
Cyclization is monitored through heat evolution, which occurs during polymerization
of the monomer used to swell the beads.
As
a
mechanically-inactive enediyne control, mono-
methacrylate 25 was prepared and incorporated into PMMA
methacroyl chloride
TEA, CH2Cl2, -78 °C
65%
O
OH
O
H3C
CH3
O
HO
O
24
1
1) Ac2O, NaOH, pH 7.8
2) methacroyl chloride, TEA, CH2Cl2, -78 °C
75%
O
O
CH3
H3C
O
O
25
Scheme 4. Preparation of bismethacrylate 24 and monomethacrylate 25.

C.R. Hickenboth et al. / Tetrahedron 64 (2008) 8435–8448
8441
0.8
0.6
0.4
0.2
0
0.15
24
25
24
0.1
25
No enediyne (EGDMA only)
0.05
0
-0.05
-0.1
-0.15
-0.2
25
45
65
85
105
25
45
65
85
105
T (C)
125
145
165
T (C)
Figure 9. DSC traces of MMA polymerization initiated by beads crosslinked either with
enediyne dimethacrylate 24 or with EGDMA and including pendant enediyne 25.
Three traces are shown for each type of bead.
Figure 10. DSC traces of butyl methacrylate polymerization initiated by photo-
polymerized polymer networks crosslinked either with enediyne dimethacrylate 24,
with EGDMA and including pendant enediyne 25, or only with EGDMA.
microspheres as above (Scheme 4). Because monomethacrylate 25
is incorporated into the polymer matrix as a pendant group, stress
applied to the polymer backbone is not applied across the enediyne
skeleton and is not expected to affect the temperature of BC. In this
case, ethylene glycol dimethacrylate (EGDMA) is added as a cross-
linker. This control will allow the isolation and identification of
effects caused by thermally-activated BC and stress-activated BC. As
a second control, microspheres were prepared crosslinked only
with EGDMA and containing no enediyne. These control micro-
spheres allow the isolation of thermal background polymerizations
from polymerizations initiated by BC.
Microspheres containing the enediyne crosslinker, pendant
control, or ethylene glycol crosslinks were washed by swelling
them in CH2Cl2 for 4 h, then decanting the solvent. Residual solvent
was then removed under vacuum. This washing step was necessary
to remove the excess BPO initiator from the polymer matrix, which
homolyzes in the same temperature region as BC and becomes
a competitive initiator. The washed microspheres were then placed
in DSC pans, swollen in MMA under argon for 24 h at room tem-
perature, then analyzed by DSC. It was found that microspheres
containing both crosslinker 24 and pendant control 25 exotherm at
temperatures above 100 ꢂC. No exotherm was observed for the
control EGDMA-crosslinked microspheres in this region. This result
suggests that the exotherm observed upon DSC analysis of the
enediyne-containing microspheres was due to polymerization of
MMA initiated by BC. Unfortunately, the differences in the tem-
peratures of exotherm for crosslinker 24 and pendant group 25 are
not statistically significant (Fig. 9), and no conclusions can be drawn
as to the role of mechanical stress in activating the enediyne
initiators.
CH2Cl2. Another reason is that swelling did not apply enough force
to the crosslinks for a significant temperature change to be detected
by DSC.
To investigate whether the enediyne crosslinks were being
prematurely activated, a photopolymerization scheme was worked
out that does not require the use of a thermally active initiator. The
absence of a thermal initiator eliminates the need for a washing
step. These samples were prepared by irradiation of mixtures of the
crosslinker, methyl acrylate (600:1 molar ratio of crosslinker to
monomer), and 2,2-dimethoxy-2-phenylacetophenone photo-
initiator in shallow glass channels. Samples of the resulting rubbery
polymer were swollen in MMA and analyzed by DSC. The results are
shown in Figure 10. It can be seen that the DSC curves for the
exotherm of polymerization occur at the same temperature. This
suggests that preactivation of the enediyne crosslinks is not the
reason for the absence of mechanical activation.
Next it was examined whether the magnitude of stress being
applied to the crosslinks by swelling is sufficient to observe a tem-
perature reduction by DSC. Previous results obtained within our
group suggest that azo crosslinkers are sensitive to mechanical
shear created by ultrasound.7 Thus, it was hypothesized that if no
temperature difference was observed between azo linker 26, which
acts as a crosslinker, and pendant azo group 27 (Scheme 5), then
insufficient stress was being applied to the crosslinks in the swollen
gel to detect a temperature shift by DSC.
The preparation of both azo crosslinker 26 and pendant azo
group 27 began with commercially-available azo diol 28. Treatment
of this material with methacroyl chloride and TEA yielded bisme-
thacrylate linker 26 (Scheme 5). Pendant control linker 27 was
prepared from azo compound 28 by treatment with Ac2O and
pyridine, followed by subsequent treatment with methacroyl
chloride and TEA. These linkers were incorporated into PMMA
microspheres, swollen in MMA under Ar, and analyzed by DSC.
There are several reasons why this might be the case. Although
unlikely, it is possible that the enediynes were being prematurely
activated in the washing stage when the beads were swollen with
O
CH3
Cl
O
H C
CH3
N
3
O
O
H C
H
N
CH3
N
3
H
N
N
OH
H3C
N
O
HO
N
H
O
N
H
CH3
TEA, CH2Cl2
H3C CH3
O
H3C CH3
O
O
28
26
O
O
H C
CH3
3
H
1) Ac2O, pyridine
N
N
O
H3C
O
N
N
CH3
O
2)
H
H3C CH3
O
O
TEA, CH2Cl2
CH3
Cl
27
Scheme 5. Preparation of azo dimethacrylate crosslinker 26 and pendant azo methacrylate 27.

8442
0.6
C.R. Hickenboth et al. / Tetrahedron 64 (2008) 8435–8448
was stored over 4 Å MS. All moisture or air sensitive reactions were
completed under an atmosphere of dry nitrogen or argon.
26
27
Analytical TLC was performed on Kieselgel F254 precoated TLC
plates, and visualized with UV light at 254 nm. Flash chromatog-
raphy was conducted with silica gel 60 (230–400 mesh) from EM
science. The 1H and 13C NMR spectra were recorded on Varian Unity
400 or 500 MHz spectrometers in the University of Illinois’ NMR
laboratory. The residual solvent protons were used as an internal
standard. Chemical shifts are reported in parts per million (ppm).
Coupling constants (J) are reported in hertz (Hz), and splitting
patterns are designated as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), and br (broad). MS were obtained through
the Mass Spectrometry Facility, SCS, University of Illinois. CHN el-
emental analysis (EA) was performed in the Microanalytical Service
Laboratory with a CE440 instrument (Exeter Analytical, Inc.). DSC
analysis was performed on a Mettler Toledo DSC instrument using
No azo (EGDMA only)
0.4
0.2
0
30
60
90
120
Temperature (°C)
40 m
L aluminum crucibles and a heating rate of 5 or 10 ꢂC per min.
Figure 11. DSC traces of PMMA microspheres crosslinked either with azo dimetha-
crylate 26, with EGDMA and including pendant azo 27, or only with EGDMA.
4.1.1. 4-Bromo-3-iodophenol
A 250 mL round-bottomed flask equipped with a magnetic
stirrer and rubber septa was purged with N2, charged with 4-
bromo-3-iodoanisole47 (9.12 g, 29.2 mmol), and dissolved in dry
CH2Cl2 (95 mL). Added over 1 min was a boron trifluoride–dimethyl
sulfide complex (15.4 mL, 146 mmol). This mixture was stirred
overnight (approximately 12 h), then the solvent was removed
under a stream of N2. The residue was partitioned between EtOAc
(50 mL) and 2 M HCl (50 mL). The layers were separated, and the
aqueous layer was extracted with EtOAc (2ꢁ150 mL). The combined
organic layers were washed with 2 M HCl (150 mL), dried over
Na2SO4 and concentrated under vacuum. Purification by flash
chromatography (10:1 hexanes/EtOAc, silica) yielded 4-bromo-3-
iodophenol (8.7 g, 100%) as off-white needles: mp 83–84 ꢂC; TLC Rf
The results of the DSC studies are shown in Figure 11. Both azo
crosslinker 26 and pendant azo control 27 yield an exotherm of
polymerization that begins to occur at about 80–90 ꢂC. This exo-
therm is absent in the EGDMA microspheres, suggesting that the
azo group is responsible for the polymerization. Since the onset of
the exotherm in azo crosslinker 26 and pendant azo group 27 oc-
curs at similar temperatures, it was concluded that the bulk ma-
terial test, coupled with the DSC analysis, is not sensitive enough to
detect the shifts in the exotherm under the weak stress applied
from the swelling of polymer networks. Therefore, a different ex-
perimental setup is needed to study stress-induced cyclo-
aromatization reactions.
0.22 (5:1 hexanes/EtOAc); 1H NMR (CDCl3, 400 MHz)
J¼8.6 Hz), 7.37 (1H, d, J¼2.7 Hz), 6.71 (1H, dd, J¼3, 8.8 Hz), 4.91 (1H,
d 7.43 (1H, d,
3. Conclusions
s); 13C NMR (CDCl3,100 MHz)
d 154.9,133.1,127.3,126.7,117.4,101.3;
Enediyne-based mechanical triggers have been designed and
synthesized. Computational studies suggest that the deformation
of distance d is highly dependant on the shape of the enediyne and
the orientation of the bonds linking the mechanophore to the
polymer backbone. The spring constant k for the desired de-
formation in enediyne 1 was computationally determined to be
36.8 N/m. This suggests that the deformation d is represented by
a compliant spring, much more deformable than the stretching of
a C–C bond.
Three enediynes studied computationally were successfully
synthesized. The thermal BC reactions for these linkers were
studied by DSC, and found to be consistent with the predicted
thermal sensitivity 3>2>1 based on known substituent effects.
However, upon incorporation of the enediynes into a polymer
matrix as crosslinks, no definitive stress activation was observed.
Through experiments with mechanically-sensitive azo units, it was
concluded that swelling alone produced insufficient force to yield
a large enough reduction in onset temperature to be detectable by
DSC. Therefore, we were unable to draw any conclusions about the
stress-sensitivity of enediynes. A different testing scheme is needed
that will apply more stress in a controlled manner.7,12,14
LRMS (EI, 70 eV) m/z 299 ([Mþ2]þ), 297 (Mþ), 171 ([MꢀI]þ); HRMS
(EI, 70 eV) calcd for C6H4BrIO 297.8490, found 297.8483; EA calcd
for C6H4BrIO C 24.11, H 1.35, found C 24.15, H 1.26.
4.1.2. 1-Bromo-2-iodo-4-(2-tetrahydropyranyloxy)benzene 5
A 200 mL round-bottomed flask equipped with a magnetic
stirrer and rubber stopper was charged with 4-bromo-3-iodophe-
nol (8.34 g, 28.0 mmol) and placed under a N2 atmosphere. Added
to the flask was CH2Cl2 (112 mL), followed by 3,4-dihydropyran
(13.5 mL, 140 mmol). The resulting mixture was cooled in an ice
water bath and pTSA monohydrate (56 mg, 0.280 mmol) was
added. After 20 min the cooling bath was removed. After 2 h of
stirring the mixture was poured onto diethyl ether (170 mL). The
contents were then diluted with a 1:2:1 mixture of saturated so-
dium bicarbonate/H2O/brine (170 mL). The layers were separated
and the aqueous phase was extracted with diethyl ether (200 mL).
The combined organics were washed with saturated sodium bi-
carbonate (200 mL) and brine (200 mL), then dried over Na2SO4.
The solvent was removed under vacuum, yielding yellow crystals,
which were recrystallized from hot methanol yielding 5 (7.48 g,
20.4 mmol, 73%) as white needles: mp 76–77 ꢂC; 1H NMR (CDCl3,
400 MHz)
d
7.57 (1H, d, J¼2.77 Hz), 7.46 (1H, d, J¼8.9 Hz), 6.92 (1H,
4. Experimental
4.1. General
dd, J¼2.9, 9.0 Hz), 5.37 (1H, t, J¼3.1 Hz), 3.82 (1H, m), 3.61 (1H, m),
1.95 (1H, m), 1.83 (2H, m), 1.75–1.54 (3H, m). EA calcd for
C11H12BrIO2 C 34.49, H 3.16, found C 34.5, H 3.12.
Unless otherwise stated, all starting materials and reagents were
obtained from commercial suppliers and used without further
purification. Reagent grade ether was purchased from Malinckrodt
and anhydrous methylene chloride was purchased from Acros. THF
was distilled from sodium immediately before use, and dry CH2Cl2
4.1.3. 1-Bromo-2-(triisopropylsilylethynyl)-4-(2-
tetrahydropyranyloxy)benzene 6
A Schlenck flask equipped with a magnetic stirrer, a Teflon
stopcock and under an Ar atmosphere was charged with 5 (4.33 g,
11.82 mmol), PdCl2(PPh3)2 (0.415 g, 0.591 mmol), and CuI (0.225 g,

C.R. Hickenboth et al. / Tetrahedron 64 (2008) 8435–8448
8443
1.18 mmol). Added was a degassed solution of triisopropylsilyl-
acetylene (2.26 g, 12.41 mmol) in TEA (23 mL). The resulting yellow
solution was stirred for about 15 h, at which point the solvent was
removed under vacuum. The residue was partitioned between
saturated aqueous ammonium chloride (50 mL) and diethyl ether
(50 mL). The layers were separated, and the aqueous layer was
extracted with diethyl ether (3ꢁ50 mL). The combined organic
layers were washed with saturated aqueous ammonium chloride
(3ꢁ50 mL) and dried over Na2SO4. Vacuum filtration and removal
of the solvent under vacuum yielded a dark oil, which was purified
5.45 (1H, t, J¼3.05 Hz), 3.84 (1H, m), 3.61 (1H, m), 3.16 (1H, s), 1.98
(1H, m), 1.85 (2H, m), 1.67 (2H, m), 1.59 (1H, m), 1.14 (18H, d,
J¼11.3 Hz); 13C NMR (CDCl3, 125 MHz)
d 157.0, 133.9, 128.0, 120.2,
118.4, 116.8, 104.9, 96.3, 95.2, 82.5, 79.8, 62.0, 30.3, 18.9, 18.6, 11.5;
LRMS (EI, 70 eV) m/z 382 (Mþ), 339 ([MꢀC3H7]þ), 255, 85 (C5H9Oþ);
HRMS (EI, 70 eV) calcd for C24H34O2Si 382.2328, found 382.2336;
HPLC (1.0 mL/min, 100% hexane, 40 min, retention time 11.9 min)
indicates >95% purity.
4.1.6. 1-[(tert-Butyldimethylsilyl)oxy-6-[4-(2-tetrahydro-
by flash chromatography (hexanes/silica) to yield
11.0 mmol, 93%) as a colorless oil and with only a trace of the
bromide coupled product by NMR: 1H NMR (CDCl3, 500 MHz)
7.42
(1H, d, J¼8.8 Hz), 7.20 (1H, d, J¼2.8 Hz), 6.89 (1H, dd, J¼2.9, 8.8 Hz),
5.40 (1H, t, J¼3.0 Hz), 3.84 (1H, td, J¼3.0, 11.1 Hz), 3.61 (1H, m), 1.97
(1H, m), 1.87 (2H, m), 1.54–1.74 (3H, m), 1.15 (21H, s); 13C NMR
6
(4.64 g,
pyranyloxy)-2-(triisopropylsilylethynyl)phenyl]hex-5-yn-
3-ol 8
d
A 50 mL two-necked round-bottomed flask equipped with
a magnetic stirrer was flame-dried under Ar, then charged with 8
(0.48 g, 1.25 mmol) and freshly distilled THF (25 mL). This solution
was cooled in an isopropanol-dry ice bath, then nBuLi (0.862 mL of
1.6 M solution in hexanes, 1.38 mmol) was added dropwise via
syringe pump at a rate of 1 drop per 5 s. After complete addition,
stirring continued for 1 h then boron trifluoride etherate (0.207 mL,
1.63 mmol) was added all at once. After 15 min of stirring, 1-[(2-
tert-butyldimethylsilyl)oxy]ethyloxirane48 (0.254 g, 1.25 mmol)
was added dropwise, and stirring with cooling continued for
40 min, then the reaction was warmed to room temperature and
quenched with a 3:1 solution of saturated ammonium chloride/
water (25 mL) and diluted with diethyl ether. The layers were
separated and the aqueous layer was extracted with diethyl ether
(2ꢁ25 mL). The combined organic layers were dried over Na2SO4,
concentrated under vacuum, and purified by flash chromatography
(10:1 hexanes/EtOAc, silica) yielding 9 (0.564 g, 0.97 mmol, 77%) as
(CDCl3, 125 MHz) d 156.0, 133.1, 126.4, 121.8, 118.5, 117.6, 104.9, 96.5,
96.1, 62.0, 30.3, 25.3, 18.9, 18.6, 11.5; LRMS (EI, 70 eV) m/z 354
([Mþ2]ꢀC5H9Oþ), 352 ([MꢀC5H9O]þ), 85 (C5H9Oþ); HRMS (CI, CH4)
calcd for C22H34BrO2Si [MþH]þ 437.1511, found 437.1511; HPLC
(1.0 mL/min, 100% hexanes, 40.0 min, retention time 15.3 min) in-
dicates >98% purity.
4.1.4. 2-(Triisopropylsilylethynyl)-1-(trimethylsilylethynyl)-4-(2-
tetrahydropyranyloxy)benzene 7
A Schlenck flask equipped with a magnetic stirrer and Teflon
stopcock, and under Ar was charged with ZnBr2 (5.2 g, 23.1 mmol),
diisoproplyamine (3.23 mL, 23.1 mmol), Pd(PtBu3)2 (39 mg,
0.077 mmol), and DMF (23 mL). This was stirred for 5 min, then
added were 6 (1.62 g, 3.85 mmol) and TMS acetylene (3.3 mL,
23.1 mmol). The resulting mixture was stirred overnight, at which
point the reaction was poured onto saturated aqueous ammonium
chloride (25 mL). The mixture was diluted with diethyl ether
(25 mL). The layers were separated, and the aqueous layer was
extracted with diethyl ether (2ꢁ25 mL). The combined organic
layers were washed with saturated aqueous ammonium chloride
(50 mL) and dried over Na2SO4. Vacuum filtration and removal of
solvent under vacuum yielded a dark oil, which was purified by
flash chromatography (100% hexanes/50:1 hexanes/EtOAc, silica)
to yield 7 (1.64 g, 3.61 mmol, 94%) as a yellow oil: 1H NMR (CDCl3,
a yellow oil: 1H NMR (CDCl3, 500 MHz)
d
7.30 (1H, d, J¼8.6 Hz), 7.12
(1H, d, J¼2.6 Hz), 6.92 (1H, dd, J¼2.7, 8.8 Hz), 5.45 (1H, t, J¼3.0 Hz),
4.04 (1H, m), 3.92 (1H, m), 3.84 (2H, m), 3.61 (1H, dt, J¼4.3, 11.1 Hz),
2.67 (1H, dd, J¼5.7, 17 Hz), 2.56 (1H, dd, J¼7.6, 17 Hz), 1.97 (2H, m),
1.87 (2H, m), 1.77 (1H, m), 1.54–1.74 (3H, m), 1.14 (21H, s), 0.90 (9H,
s), 0.08 (6H, s); 13C NMR (CDCl3, 125 MHz)
d 165.3, 133.5, 127.1,
120.4, 119.7, 116.9, 105.7, 96.3, 94.4, 89.2, 81.4, 70.9, 62.5, 62.0, 37.6,
30.3, 28.5, 26.3, 25.2, 18.9,18.6, 18.3,11.5, ꢀ5.4; LRMS (EI, 70 eV) m/z
585 (Mþ), 566 ([MꢀH2O]þ), 527 ([MꢀC3H7]þ), 500 ([MꢀC5H9O]þ);
HRMS (EI, 70 eV) calcd for C34H56O4Si2 584.3713, found 584.3714;
HPLC (1.0 mL/min, 10% EtOAc in hexanes, retention time 7.4 min)
indicates >95% purity.
500 MHz)
d
7.37 (1H, d, J¼8.6 Hz), 7.12 (1H, d, J¼2.6 Hz), 6.93 (1H,
dd, J¼2.7, 8.7 Hz), 5.43 (1H, t, J¼3.14 Hz), 3.83 (1H, m), 3.61 (1H, m),
1.98 (1H, m), 1.84 (2H, m), 1.68 (2H, m), 1.59 (1H, m), 1.26 (1H, m),
1.16 (18H, d, J¼11.3 Hz), 0.22 (8H, s); 13C NMR (CDCl3, 125 MHz)
4.1.7. 6-[4-(2-Tetrahydropyranyloxy)-2-ethynylphenyl]-3-(2-
tetrahydropyranyloxy)hex-5-yn-1-ol 10
d
156.7, 134.4, 127.2, 120.6, 119.1, 116.8, 105.3, 103.7, 96.6, 96.3, 94.8,
A 200 mL round-bottomed flask equipped with a magnetic
stirrer and rubber septum was purged with a nitrogen atmosphere,
then charged with 9 (1.22 g, 2.09 mmol) and dry CH2Cl2 (8.3 mL).
This solution was cooled in an ice bath and added was 3,4-dihy-
dropyran (1.0 mL, 10.4 mmol), followed by pTSA monohydrate
(40 mg, 0.209 mmol). The resulting solution was stirred with
cooling for 2 h, then poured onto saturated aqueous NaHCO3
(10 mL) and diethyl ether (10 mL). The layers were separated, and
the aqueous layer was extracted with diethyl ether (3ꢁ25 mL). The
combined organics were washed with saturated aqueous NaHCO3
(25 mL) and brine (25 mL), then dried over Na2SO4. The solvent was
removed under vacuum yielding an oil, which was taken up in THF
(21 mL) and placed in a 250 mL round-bottomed flask equipped
with a magnetic stirrer and rubber stopper. Added all at once was
TBAF (5.21 mL of 1.0 M solution in THF, 5.21 mmol), and the
resulting solution was stirred. After 24 h the reaction was parti-
tioned between saturated aqueous ammonium chloride and diethyl
ether. The layers were separated and the aqueous layer was
extracted with diethyl ether (2ꢁ50 mL). The combined organics
were washed with brine (50 mL) and dried over Na2SO4. The sol-
vent was removed under vacuum and the residue was purified by
flash chromatography (4:1 hexanes/EtOAc/1:1 hexanes/EtOAc,
62.0, 30.3, 25.3, 19.0, 18.6, 11.5, 0.2; LRMS (EI, 70 eV) m/z 454 (Mþ),
411 ([MꢀC3H7]þ), 370 ([MꢀC5H9O]þ), 285, 243, 128, 84 (C5H9Oþ);
HRMS (EI, 70 eV) calcd for C27H42O2Si2 454.2723, found 454.2716;
HPLC (1.0 mL/min, 2.5% EtOAc/hexane, 20.0 min, retention time
5.4 min) indicates >96% purity.
4.1.5. 1-Ethynyl-2-(triisopropylsilylethynyl)-4-(2-
tetrahydropyranyloxy)benzene 8
To a 50 mL round-bottomed flask equipped with a magnetic
stirrer was added THF (6.6 mL), MeOH (6.6 mL), and 7 (0.6 g,
1.32 mmol). Added dropwise was a solution of aqueous LiOH (1 M,
4.25 mL). The resulting cloudy solution was stirred and the reaction
progress was followed by TLC. After the starting material was
consumed (approximately 40 min) the reaction was diluted with
water (20 mL) and diethyl ether (20 mL). The layers were separated
and the aqueous layer was extracted with diethyl ether (3ꢁ20 mL).
The combined organic layers were dried over Na2SO4 and con-
centrated under vacuum. The residue was purified by flash chro-
matography (100% hexane/10:1 hexane/EtOAc) yielding 8 (0.48 g,
1.25 mmol, 95%) as a yellow oil: 1H NMR (CDCl3, 500 MHz)
(1H, d, J¼8.8 Hz), 7.15 (1H, d, J¼2.6 Hz), 6.95 (1H, dd, J¼2.5, 8.7 Hz),
d 7.38

8444
C.R. Hickenboth et al. / Tetrahedron 64 (2008) 8435–8448
silica) yielding 10 (0.71 g, 1.85 mmol, 89%) as a light yellow oil:
LRMS (EI, 70 eV) m/z 398 (Mþ), 314 (MꢀC5H9Oþ), 85 (C5H9Oþ);
HRMS (EI, 70 eV) calcd for C24H30O5 398.2093, found 398.2099;
HPLC (1.0 mL/min, 33% EtOAc in hexanes, retention time 17.4 min)
indicates >95% purity.
mmol diol). Acetic anhydride (5 mL/mmol diol) was then added,
and the resulting solution was stirred for 6 h. Methanol was then
added, and stirring was continued for an additional 1 h. The solvent
was then removed, and the residue was partitioned between EtOAc
and water. The layers were separated, and the aqueous layer was
extracted with two portions of EtOAc. The combined organics were
washed with 1 M HCl and saturated NaHCO3, then dried over
Na2SO4. The solvent was removed under vacuum, to yield the crude
diacetate. Unless otherwise indicated, purity was determined by
NMR and was found to be sufficiently pure for further use.
4.1.8. 1-Iodo-6-[4-(2-tetrahydropyranyloxy)-2-ethynylphenyl]-3-
(2-tetrahydropyranyloxy)hex-5-yne 11
A 25 mL two-necked round-bottomed flask was equipped with
a magnetic stirrer and rubber stopper and purged with a nitrogen
atmosphere. Added to the flask was PPh3 (0.613 g, 2.43 mmol),
imidazole (0.477 g, 7.01 mmol), and dry CH2Cl2 (14 mL). This was
stirred until complete dissolution of all solid material. Then the
solution was cooled in an ice water bath. I2 (0.593 g, 2.34 mmol)
was then added, and the resulting mixture was stirred for 16 min
with cooling, yielding a white suspension. Added was a solution of
10 (0.449 g, 1.17 mmol) in CH2Cl2 (6.9 mL). This reaction mixture
was warmed to room temperature and allowed to stir for 19 h. The
solvent was removed under vacuum and the thick yellow residue
was immediately purified by flash chromatography (10:1 hexanes/
EtOAc, silica) yielding 11 (0.406 g, 0.800 mmol, 68%) as a colorless
oil: LRMS (EI, 70 eV) m/z 508 (Mþ), 484, 446, 424 ([MꢀC5H9O]þ),
382 ([MꢀI]þ), 85 (C5H9Oþ); HRMS (EI, 70 eV) calcd for C24H29IO4
508.1111, found 508.1097.
4.3. General procedure for the preparation of dimethacrylates
from diols
To a 50 mL two-necked round-bottomed flask equipped with
a magnetic stirrer and rubber septa and purged with Ar were added
the diol (1 equiv) and CH2Cl2 (5 mL/mmol diol). The resulting sus-
pension was cooled in a dry ice/acetone bath, then added was TEA
(16 equiv), followed by a solution of methacroyl chloride (6 equiv)
in CH2Cl2 (1 mL/mmol diol). The resulting solution was warmed
slowly to room temperature overnight, then poured onto saturated
sodium bicarbonate and CH2Cl2. The layers were separated and the
aqueous layer was extracted with two portions of CH2Cl2. The
combined organics were washed with saturated sodium bi-
carbonate then dried over Na2SO4. The solvent was removed under
vacuum to yield the crude dimethacrylate. Unless otherwise in-
dicated, purity was determined by NMR and was found to be suf-
ficient for further use.
4.1.9. 3,4-(3-Hydroxybenzo)cyclodec-3-ene-1,5-diyn-8-ol 1
A flame-dried sealed tube was placed under an Ar atmosphere,
then charged with a solution of 11 (0.598 g, 1.18 mmol) in freshly
distilled THF (17.6 mL). This solution was cooled in a dry ice/acetone
bath and a solution of LDA (2.6 mL of 0.56 M solution in THF,
1.41 mmol) was added dropwise. The reaction mixture was stirred
for 1 h, then HMPA (1.43 mL, 8.23 mmol) was added all at once and
the reaction immediately turned dark blue. The cooling bath was
removed and the mixture was stirred for 24 h at room temperature,
then quenched with brine (20 mL) and diluted with diethyl ether
(20 mL). The layers were separated, and the aqueous layer was
washed with diethyl ether (3ꢁ30 mL). The combined organics were
washed with brine and dried over Na2SO4. The solvent was re-
moved under vacuum, and the residue was passed through a short
silica plug, eluting with CHCl3, to yield the diprotected macrocycle
(0.249 g, 0.654 mmol, 56%) as a yellow oil with satisfactory LRMS
analysis (FD 380 (Mþ)). It was dissolved in 1:1 MeOH/THF (6 mL)
and placed in a 20 mL scintillation vial equipped with a magnetic
stirrer and plastic screw cap. Added was pTSA monohydrate (13 mg,
0.07 mmol). After 1 h of stirring the reaction was quenched with
saturated aqueous sodium bicarbonate (5 mL) and water (2 mL),
then diluted with diethyl ether (5 mL). The layers were separated,
and the aqueous layer was extracted with diethyl ether (3ꢁ5 mL).
The combined organics were washed with saturated aqueous so-
dium bicarbonate and brine (5 mL each), then dried over Na2SO4.
The solvent was removed under vacuum and the residue was pu-
rified by flash chromatography (3:1 hexanes/EtOAc/3:2 hexanes/
EtOAc, silica) yielding 1 (72 mg, 0.340 mmol, 52%) as an off-white
4.3.1. 8-Acetoxy-3,4-(3-acetoxybenzo)cyclodec-3-ene-1,5-diyne 21
Prepared using the general procedure for the preparation of
diacetates. Recrystallization of the solid residue from methanol
gave 21 (70.8 mg, 0.238 mmol, 58%) as white needles: mp 138–
140 ꢂC; 1H NMR (CDCl3, 500 MHz)
d, J¼2.4 Hz), 6.92 (1H, dd, J¼2.3, 8.5 Hz), 4.95 (1H, m), 2.78 (2H, m),
2.67 (1H, m), 2.57 (1H, ddd, J¼2.2, 5.5, 17.8 Hz), 2.28 (3H, s), 2.25
(1H, m), 2.07 (1H, m), 2.06 (3H, s); 13C NMR (125 MHz, CDCl3)
d
7.29 (1H, d, J¼8.2 Hz), 7.03 (1H,
d
170.6, 169.2, 150.0, 130.6, 129.3, 126.5, 121.7, 121.1, 100.7, 93.5, 84.0,
82.7, 75.1, 37.7, 27.4, 21.4, 21.3, 19.4; LRMS (EI, 70 eV) m/z 296 (Mþ),
236 ([MꢀCH3COOH]þ),194 ([MꢀC4H6O3]þ); EA calcd for C18H16O4 C
72.96, H 5.44, found C 72.97, H 5.34.
4.3.2. 8-Methacroyloxy-3,4-(3-methacroyloxybenzo)cyclodec-3-
ene-1,5-diyne 24
Prepared using the general procedure for the preparation of
dimethacrylates. The crude residue was purified by flash chroma-
tography (20:1 hexane/EtOAc, silica) to yield a white solid. This was
recrystallized from hexane, to yield 25 (0.114 g, 0.325 mmol, 65%)
as a white solid: mp 95 ꢂC (dec); 1H NMR (CDCl3, 500 MHz)
d 7.32
(1H, d, J¼8.5 Hz), 7.07 (1H, d, J¼2.2 Hz), 7.00 (1H, dd, J¼2.2, 8.4 Hz),
6.33 (1H, app quintet, J¼1.1 Hz), 6.11 (1H, m), 5.76 (1H, quintet,
J¼1.5 Hz), 5.59 (1H, quintet, J¼1.6 Hz), 5.03 (1H, m), 2.79 (3H, m),
2.59 (1H, ddd, J¼2.2, 5.8, 17.6 Hz), 2.31 (1H, m), 2.12 (1H, dquintet,
J¼2.3, 14.8 Hz), 2.04 (3H, app t, J¼1.1 Hz), 1.94 (3H, app t, J¼1.0 Hz);
solid: 1H NMR (CD3OD, 400 MHz)
d
7.10 (1H, d, J¼8.3 Hz), 6.67 (1H,
d, J¼2.2 Hz), 6.65 (1H, dd, J¼2.6, 8.3 Hz), 4.92 (2H, br s), 3.92 (1H,
13C NMR (CDCl3, 125 MHz)
d 166.9, 165.6, 150.3, 136.4, 135.8, 130.6,
m), 2.60 (2H, m), 2.48 (2H, m), 2.16 (1H, m), 2.04 (1H, m); 13C NMR
129.2, 127.9, 126.5, 126.2, 121.8, 121.1, 100.8, 93.5, 84.0, 82.8, 75.2,
37.5, 27.4, 19.4, 18.55, 18.50; LRMS (EI, 70 eV) m/z 348 (Mþ), 262
([MꢀC4H5O2]þ); HRMS (EI, 70 eV) calcd for C22H20O4 348.1354,
found 348.1362; EA calcd C 75.84, H 5.79, found C 75.7, H 5.65.
(CD3OD,100 MHz) d 157.0,130.4,129.2,120.2,114.9,114.4, 99.0, 91.8,
83.7, 82.7, 73.4, 39.7, 29.9, 19.2; LRMS (EI, 70 eV) m/z 212 (Mþ), 183,
169, 139; HRMS (EI, 70 eV) calcd for C14H12O2 212.0837, found
212.0840.
4.3.3. 8-Methacroyloxy-3,4-(3-acetoxybenzo)cyclodec-3-ene-1,5-
diyne 25
To a 10 mL conical reactor equipped with a magnetic stirrer and
Teflon septum was added a solution of diol 3 (94.1 mg, 0.444 mmol)
in isopropanol (3 mL). To this solution was added a mixture of
NaOH (48.8 mg, 1.22 mmol) in water (0.6 mL). This was vigorously
4.2. General procedure for the preparation of diacetates from
diols
In a scintillation vial equipped with a magnetic stirrer and
plastic cap were added the diol (1 equiv) and pyridine (20 mL/

C.R. Hickenboth et al. / Tetrahedron 64 (2008) 8435–8448
8445
stirred for 5 min, then added was acetic anhydride (0.12 mL,
1.22 mmol). The reaction progress was followed by TLC and, after
complete disappearance of the starting material (about 30 min) the
mixture was concentrated under vacuum, then partitioned be-
tween EtOAc (10 mL) and water (10 mL). The layers were separated,
and the aqueous layer was extracted with EtOAc (3ꢁ10 mL). The
combined organics were washed with brine and dried over Na2SO4.
The solvent was removed under vacuum to yield a yellow solid. This
was placed in a 10 mL conical reactor equipped with a magnetic
stirrer and Teflon septa. The flask was purged with nitrogen, then
CH2Cl2 (2.2 mL) was added. The suspension was cooled in a dry ice/
acetone bath, then triethylamine (0.43 mL, 3.1 mmol) was added,
followed by the dropwise addition of a solution of methacroyl
chloride (0.26 mL, 2.66 mmol) in CH2Cl2 (0.5 mL). The resulting
solution was allowed to warm to room temperature and stir over-
night. The reaction was poured onto 5% NaHCO3 (5 mL). This was
extracted with CH2Cl2 (3ꢁ5 mL). The combined organics were
washed with water (10 mL), saturated NaHCO3 (10 mL), and brine
(10 mL), then dried over Na2SO4. The solvent was removed under
vacuum, and the residue was purified by flash chromatography
(20:1 hexane/EtOAc, silica), yielding 25 (0.108 g, 0.333 mmol, 75%)
as a white solid that was used without further purification. A small
amount of material was recrystallized from methanol for analysis:
then added to the mixture, and the resulting suspension was stirred
for 12 h, then poured onto saturated ammonium chloride (50 mL)
and ether (50 mL). The layers were separated and the aqueous
phase was washed with ether (3ꢁ50 mL). The combined organics
were washed with saturated ammonium chloride (50 mL) and
water (50 mL), dried over Na2SO4, and concentrated under reduced
pressure. The resulting dark oil was taken up in THF (100 mL) and
MeOH (2.2 mL) and placed in a 200 ml round-bottomed flask, then
added was a solution of TBAF in THF (5.45 mL, 5.45 mmol). This was
stirred for 2 h, then poured onto saturated ammonium chloride
(100 mL) and diluted with diethyl ether (100 mL). The layers were
separated, and the aqueous layer was extracted with diethyl ether
(3ꢁ100 mL). The combined organic layers were dried over Na2SO4,
concentrated under vacuum, and purified by flash chromatography
yielding 14 (1.19 g, 4.01 mmol, 74%) as a yellow oil: 1H NMR (CDCl3,
500 MHz)
d
7.37 (1H, d, J¼8.7 Hz), 7.08 (1H, d, J¼2.5 Hz), 6.90 (1H,
dd, J¼2.6, 8.5 Hz), 5.40 (1H, t, J¼3.2 Hz), 3.83 (1H, ddd, J¼1.2, 8.4,
10.4 Hz), 3.71 (2H, t, J¼6.4 Hz), 3.60 (1H, dtd, J¼1.3, 4.1,11.2 Hz), 3.19
(1H, s), 2.50 (2H, t, J¼6.9 Hz),1.96 (1H, m),1.83 (2H, m),1.78 (2H, m),
1.54–1.74 (6H, m); 13C NMR (CDCl3, 125 MHz)
d 157.1, 133.9, 128.3,
119.6, 117.7, 116.4, 96.4, 94.4, 82.7, 79.6, 79.3, 62.6, 62.2, 31.9, 30.3,
25.3, 25.0, 19.5, 18.7; LRMS (EI, 70 eV) m/z 298 (Mþ), 214
([MꢀC5H9O]þ), 85 (C5H9Oþ); HRMS (EI, 70 eV) calcd for C19H22O3
298.1569, found 298.1561; HPLC (1.0 mL/min, 20% EtOAc/hexanes,
60 min, retention time 26.7 min) indicates >96% purity.
mp 89–91 ꢂC; 1H NMR (500 MHz, CDCl3)
d
7.30 (1H, d, J¼8.4 Hz),
7.03 (1H, d, J¼2.2 Hz), 6.96 (1H, dd, J¼2.6, 8.2 Hz), 6.11 (1H, s), 5.59
(1H, app t, J¼1.5 Hz), 5.02 (1H, m), 2.79 (3H, m), 2.58 (1H, dd, J¼1.7,
5.5 Hz), 2.31 (1H, ddd, J¼2.0, 4.8, 14.6 Hz), 2.28 (3H, s), 2.11 (1H, m),
4.3.6. 1-[2-(2-Iodoethynyl)-5-(2-tetrahydropyranyloxy)phenyl]-
hex-1-yn-6-ol 15
1.94 (3H, s); 13C NMR (125 MHz, CDCl3)
d 169.2, 166.9, 150.0, 136.4,
130.6, 129.3, 126.6, 126.2, 121.7, 121.1, 100.8, 93.5, 83.9, 82.7, 75.2,
37.5, 27.4, 21.3, 19.4, 18.5; LRMS (EI, 70 eV) m/z 322 (Mþ), 236
([MꢀC4H6O2]þ), 194 ([MꢀC6H8O3]þ); HRMS (EI) calcd for C20H18O4
322.1205, found 322.1197; EA calcd for C20H18O4 C 74.52, H 5.63,
found C 74.35, H 5.48.
A Schlenck flask equipped with a magnetic stirrer was charged
with dry THF (114 mL) and diisopropylamine (1.23 mL, 8.80 mmol).
This mixture was cooled in a dry ice/isopropanol bath, then added
was nBuLi (5.25 mL of 1.6 M solution in hexanes, 8.4 mmol). After
complete addition the cooling bath was removed and the mixture
was allowed to warm for 20 min, then the cooling bath was
replaced. Alkyne 14 (1.19 g, 3.99 mmol) was added as a solution in
THF (12 mL) and the reaction mixture immediately turned brown.
This was stirred with cooling for 2 h, then I2 (1.01 g, 3.99 mmol) was
added. The resulting orange solution was stirred with cooling for
1 h, then warmed to room temperature and diluted with saturated
Na2S2O3 (100 mL) and diethyl ether (100 mL). The layers were
separated and the aqueous layer was extracted with diethyl ether
(3ꢁ100 mL). The combined organic layers were washed with brine
(100 mL), dried over Na2SO4, and concentrated under vacuum. The
residue was purified by flash chromatography (3:1 hexanes/
EtOAc/2:1 hexanes/EtOAc, silica) yielding 15 (1.46 g, 3.46 mmol,
4.3.4. 1-[2-Bromo-5-(2-tetrahydropyranyloxy)phenyl]hex-1-yn-6-
ol 13a
A sealed tube under Ar was charged with PdCl2(PPh3)2 (37 mg,
0.331 mmol) and CuI (126 mg, 0.662 mmol). Added was a degassed
solution of 5 (2.43 g, 6.62 mmol) and 5-hexyn-1-ol (0.75 mL,
6.95 mmol) in triethylamine (13 mL). The resulting solution was
stirred for 26 h, then poured onto saturated ammonium chloride
(25 mL) and ether (25 mL). The layers were separated and the
aqueous later was extracted with ether (3ꢁ25 mL). The combined
organic phases were washed with saturated ammonium chloride
(2ꢁ50 mL), dried over Na2SO4, and concentrated under reduced
pressure. Purification of the residue by flash chromatography (3:1
hexane/EtOAc, silica) yielded 13a (1.92 g, 5.69 mmol, 86%) as a yel-
low oil and as an inseparable 47:3 ratio of the bromide/iodide: 1H
87%) as a light yellow oil: 1H NMR (CDCl3, 500 MHz)
d 7.31 (1H, d,
J¼8.6 Hz), 7.06 (1H, d, J¼2.5 Hz), 6.89 (1H, dd, J¼2.6, 8.7 Hz), 5.48
(1H, t, J¼3.4 Hz), 3.83 (1H ddd, J¼3.0, 9.9, 11.2 Hz), 3.75 (2H, t,
J¼6.3 Hz), 3.10 (m, 1H), 2.52 (2H, t, J¼7.0 Hz), 1.97 (1H, m), 1.83 (4H,
m), 1.73 (2H, m), 1.66 (2H, m), 1.60 (1H, m); 13C NMR (CDCl3,
NMR (CDCl3, 500 MHz)
d
7.36 (1H, d, J¼8.7 Hz), 7.09 (1H, d,
J¼2.97 Hz), 6.79 (1H, dd, J¼2.8, 8.8 Hz), 5.32 (1H, t, J¼3.12 Hz), 3.80
(1H, m), 3.64 (2H, t, J¼6.27), 2.68 (1H, br s), 2.45 (2H, t, J¼6.71 Hz),
1.91 (1H, m), 1.79 (2H, m), 1.43–1.75 (8H); 13C NMR (CDCl3,
125 MHz)
d 157.2, 134.0, 128.7, 119.3, 117.7, 116.2, 96.4, 94.6, 93.2,
79.7, 62.8, 62.2, 32.1, 30.3, 25.5, 25.5, 19.5, 18.7, 7.6; LRMS (EI, 70 eV)
m/z 424 (Mþ), 340 ([MꢀC5H9O]þ), 85 (C5H9Oþ); HRMS (EI, 70 eV)
calcd for C19H21IO3 424.0535, found 424.0539; HPLC (1.0 mL/min,
20% EtOAc in hexanes, retention time 29.3 min) indicated >92%
purity with an inseparable mixture of 6% starting material.
125 MHz)
d 156.0, 133.0, 12.6, 121.2, 118.0, 117.2, 96.6, 95.0, 79.9,
62.4, 62.2, 32.0, 30.4, 25.3, 25.0, 19.5, 18.7; LRMS (EI, 70 eV) m/z 354
([Mþ2]þ), 352 (Mþ), 268 ([MꢀC5H9O]þ), 85 (C5H9Oþ); HRMS (EI,
70 eV) calcd for C17H21BrO3 352.0674, found 352.0671; HPLC
(1.0 mL/min, 20% EtOAc/hexanes, 40 min, retention time 20.0 min)
indicates 94% purity.
4.3.7. 1-[2-(2-Iodoethynyl)-5-(2-tetrahydropyranyloxy)-
phenyl]hex-1-yn-6-al 16
4.3.5. 1-[2-Ethynyl-5-(2-tetrahydropyranyloxy)phenyl]hex-1-yn-6-
ol 14
A 500 mL two-necked round-bottomed flask equipped with
a magnetic stirrer and two glass stoppers was purged with N2 then
charged with a solution of 15 (1.44 g, 3.41 mmol) in dry CH2Cl2
(180 mL). This mixture was cooled in an ice bath, then PDC (12.8 g,
34.1 mmol) was added, followed by CH2Cl2 (12 mL). The resulting
orange mixture was stirred with cooling for 30 min, then warmed to
room temperature and stirred overnight. The reaction was filtered
A Schlenck flask equipped with a magnetic stirrer and Teflon
stopper and under Ar was charged with dry DMF (32 mL), 13a
(1.92 g, 5.45 mmol), and TMS acetylene (3.84 mL, 27.2 mmol). This
mixture was degassed with bubbling Ar and cooled in an ice bath.
Pd(PtBu3)2 (56 mg, 0.109 mmol) and ZnBr2 (7.35 g, 32.7 mmol) was

8446
C.R. Hickenboth et al. / Tetrahedron 64 (2008) 8435–8448
through a Celite plug, and the plug was washed with CH2Cl2
(3ꢁ500 mL). The filtrate was concentrated under vacuum and the
dark residue was purified by flash chromatography (15:1 hexanes/
EtOAc/5:1, silica) yielding 16 (1.17 g, 2.78 mmol, 82%) as a yellow
oil homogenous by TLC (Rf 0.541,1:1 hexane/EtOAc); 1H NMR (CDCl3,
d
7.38 (1H, d, J¼8.3 Hz), 7.05 (1H, d, J¼2.3 Hz), 6.97 (1H, dd, J¼2.6,
8.3 Hz), 5.56 (1H, dd, J¼2.9, 8.6 Hz), 2.48 (2H, m), 2.30 (1H, m), 2.28
(3H, s), 2.14 (2H, m), 2.11 (3H, s), 1.87 (1H, m); 13C NMR (125 MHz,
CDCl3) d 170.2,169.1,150.7,131.6,130.3,125.6,121.7,121.1,101.3, 95.1,
85.6, 81.7, 65.1, 34.9, 24.0, 21.4, 21.31, 21.28; LRMS (EI, 70 eV) m/z
296 (Mþ), 254 ([MꢀC2H2O]þ), 212 ([MꢀC4H4O2]þ), 194 (C14H10Oþ);
HRMS (EI, 70 eV) calcd for C18H16O4 296.1049, found 296.1044.
500 MHz)
d
9.90 (1H, t, J¼1.3 Hz), 7.31 (1H, d, J¼8.6 Hz), 7.06 (1H, d,
J¼2.4 Hz), 6.90 (1H, dd, J¼2.6, 8.6 Hz), 5.40 (1H, t, J¼3.2 Hz), 3.83
(1H, m), 3.60 (1H, m), 2.71 (2H, dt, J¼1.2, 7.3 Hz), 2.56 (2H, t,
J¼6.7 Hz), 1.95 (3H, q, J¼7.0 Hz), 1.84 (2H, m), 1.67 (2H, m), 1.59 (1H,
4.3.11. 6-[(tert-Butyldimethylsilyl)oxy]-1-[(2-triisopropyl-
silylethynyl)phenyl]hex-1-yn-3-ol 18
m); 13C NMR (CDCl3, 125 MHz)
d
202.3, 157.2, 134.0, 128.5, 119.5,
119.3,116.4, 96.4, 93.3, 93.2, 80.2, 62.2, 43.0, 30.3, 25.2, 21.2,19.1,18.7,
7.4; LRMS (EI, 70 eV) m/z 422 (Mþ), 338 ([MꢀC5H9O]þ), 85 (C5H9Oþ);
HRMS (EI, 70 eV) calcd for C19H19IO3 422.0379, found 422.0371;
HPLC (1.0 mL/min, 20% EtOAc in hexanes, retention time 7.1 min)
indicated 82% impurity, with the major impurity, 18%, consisting of
the terminal alkyne. The material was inconsequentially used
without further purification.
A flame-dried 50 mL round-bottomed, 2-necked flask equipped
with a magnetic stirrer and rubber stopper and under an Ar atmo-
sphere was charged with 1-(triisopropylsilylethynyl)-2-ethy-
nylbenzene39 (0.223 g, 0.791 mmol) and THF (15.8 mL). This
solution was cooled in a dry ice/acetone bath, then nBuLi (0.56 mL of
1.55 M solution in hexanes, 0.87 mmol) was added dropwise. The
resulting solution was stirred with cooling for 1 h, then 4-[(tert-
butyldimethylsilyl)oxy]butanal (0.18 g, 0.91 mmol) in THF (1 mL)
was added dropwise. This solution was stirred with cooling for 2 h,
then warmed to room temperature and stirred for an additional 1 h.
The reaction was quenched by pouring onto a mixture of 0.1 M HCl
(20 mL) and Et2O (20 mL). The layers were separated, and the
aqueous layer was extracted with Et2O (2ꢁ20 mL). The combined
organics were washed with brine and dried over Na2SO4. The sol-
vent was removed under vacuum, and the residue was placed on
a silica plug. The plug was washed with hexane (250 mL), then the
compound was eluted with 5:1 hexane/EtOAc (250 mL). The hex-
ane/EtOAc layer was concentrated under vacuum, yielding 18
(0.365 g, 0.753 mmol, 95%) as a light yellow oil: 1H NMR (500 MHz,
4.3.8. 3,4-[3-(2-Tetrahydropyranyloxy)benzo]cyclodec-3-ene-1,5-
diyn-7-ol
A 250 mL Schlenk flask was placed under an Ar atmosphere and
charged with freshly distilled THF (55.5 mL) followed by a mixture
of anhydrous CrCl2 (1.17 g, 9.49 mmol) and NiCl2 (41 mg,
0.313 mmol). The resulting suspension was cooled in an ice bath
and stirred vigorously, then a solution of aldehyde 16 (0.400 g,
0.949 mmol) in distilled THF (22 mL) was added dropwise over
several minutes. This was stirred with cooling and followed by TLC.
When the starting material was completely consumed (about
1.5 h), the reaction was quenched with saturated ammonium
chloride, then warmed to room temperature and diluted with ether
(80 mL). The layers were separated and the aqueous layer was
extracted with ether (3ꢁ80 mL). The combined organic phases
were washed with saturated ammonium chloride (2ꢁ100 mL) and
brine (100 mL), then dried over Na2SO4. Vacuum filtration and re-
moval of solvent under vacuum yielded an orange oil. Purification
by flash chromatography (10:1 hexane/EtOAc/3:1 hexane/EtOAc,
silica) yielded 3,4-[4-(2-tetrahydropyranyloxy)benzo]cyclodec-3-
ene-1,5-diyn-7-ol (0.198 g, 0.67 mmol, 70%) as an orange oil: TLC Rf
CDCl3)
(2H, m), 3.13 (1H, s),1.89 (3H, m),1.74 (1H, m),1.15 (s, 21H), 0.91 (9H,
s), 0.08 (6H, s); 13C NMR (125 MHz, CDCl3)
132.9,132.5,128.1,128.0,
d 7.47 (1H, m), 7.43 (1H, m), 7.23 (2H, m), 4.65 (1H, s), 3.70
d
126.0, 125.6, 105.6, 94.8, 94.3, 83.6, 63.4, 62.9, 35.5, 28.9, 26.1, 18.9,
18.5, 11.5, ꢀ5.2; LRMS (EI, 70 eV) m/z 484 (Mþ), 427 ([MꢀC4H9]þ),
239; HRMS (EI) calcd for C29H48O2Si2 484.3183, found 484.3192; EA
calcd for C29H48O2Si2 C 71.84, H 9.98, found C 71.71, H 10.14.
4.3.12. 3-(2-Tetrahydropyranyloxy)-1-[(2-triisopropyl-
silylethynyl)phenyl]-hex-1-yn-6-ol 19
0.1 (5:1 hexanes/EtOAc, silica); 1H NMR (CDCl3, 400 MHz)
d
7.28
(1H, d, J¼8.4 Hz), 7.03 (1H, d, J¼2.5 Hz), 6.91 (1H, dd, J¼2.2, 8.6 Hz),
5.39 (1H, t, J¼3.3 Hz), 4.63 (1H, m), 3.84 (1H, m), 3.60 (1H, m), 2.47
(2H, m), 2.15 (3H, m), 1.97 (1H, m), 1.84 (4H, m), 1.67 (2H, m); LRMS
(EI, 70 eV) m/z 296 (Mþ), 212 ([MꢀC5H8O]þ), 85 (C5H8Oþ); HRMS
(EI, 70 eV) calcd for C19H20O3 296.1412, found 296.1411.
To a scintillation vial equipped with a magnetic stirrer was
added 18 (0.32 g, 0.66 mmol), 3,4-dihydropyran (0.32 mL,
3.3 mmol), and CH2Cl2 (2.6 mL). This solution was cooled in an ice
bath, and then pTSA monohydrate (12.5 mg, 0.066 mmol) was
added. The resulting solution was stirred and followed by TLC.
Upon completion, the reaction mixture was poured onto saturated
NaHCO3 (5 mL). The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (5 mL). The combined organics were
dried over Na2SO4 and the solvent was removed under vacuum. The
resulting oil was placed in a scintillation vial equipped with
a magnetic stirrer and dissolved in THF (4 mL). TBAF (1.5 mL of
1.0 M solution in THF, 1.5 mmol) was then added, and the resulting
solution stirred overnight. The contents were partitioned between
saturated NH4Cl (10 mL) and Et2O (10 mL). The layers were sepa-
rated, and the aqueous layer was extracted with Et2O (2ꢁ10 mL).
The combined organics were dried over Na2SO4 and the solvent
was removed under vacuum. Purification of the residue by flash
chromatography (5:1 hexane/EtOAc/1:1 hexane/EtOAc, silica)
yielded 19 (0.142 g, 0.476 mmol, 72%) as a yellow oil and a mixture
of a major and a minor diastereomer (approx. 6.7:1 ratio by 1H NMR
integration of the acetal hydrogen): 1H NMR (500 MHz, CDCl3)
4.3.9. 3,4-(4-Hydroxybenzo)cyclodec-3-ene-1,5-diyn-7-ol 2
Into a 20 mL scintillation vial was placed 3,4-[4-(2-tetrahy-
dropyranyloxy)benzo]cyclodec-3-ene-1,5-diyn-7-ol
(0.582 g,
1.97 mmol). This was dissolved in a 4:2:1 mixture of AcOH/THF/H2O
(7 mL) and placed in an oil bath equilibrated at 40 ꢂC and stirred.
After 2.5 h, the solvent was removed under vacuum and the residue
was purified by flash chromatography (3:1 hexane/EtOAc, silica)
yielding 2 (0.244 g, 1.15 mmol, 58%) as an off-white solid: mp 150–
152 ꢂC; 1H NMR (CD3CN, 500 MHz)
d
7.30 (br s), 7.19 (1H, dd, J¼0.34,
8.6 Hz), 6.69 (1H, m), 6.67 (1H, d, J¼2.5 Hz), 5.34 (1H, d, J¼4.8 Hz),
4.5 (1H, dd, J¼3.1, 8.1 Hz), 3.32 (1H, br s), 2.42 (2H, m), 2.03 (3H, m),
1.70 (1H, m); 13C NMR (CD3CN, 125 MHz)
d 157.2, 131.3, 130.4, 120.0,
115.3, 115.0, 101.1, 98.1, 83.9, 81.7, 62.6, 38.3, 23.8, 20.9; LRMS (EI,
70 eV) m/z 212.1 (Mþ),194.1 ([MꢀH2O]þ), 62; HRMS (EI, 70 eV) calcd
for C14H12O2 212.0837, found 212.0841; HPLC (1.0 mL/min, 50%
EtOAc in hexanes, retention time 5.4 min) indicates >98% purity.
d
7.46 (2H, m), 7.24 (2H, m), 5.13 (1H, t, J¼3.2 Hz), 4.74 (1H, t,
J¼6.0 Hz), 3.82 (1H, m), 3.70 (2H, m), 3.53 (1H, m), 2.32 (1H, br s),
1.98–1.37 (10H, m, 12, 13); 13C NMR (CDCl3, 125 MHz)
132.7, 132.2,
4.3.10. 7-Acetoxy-3,4-(4-acetoxybenzo)cyclodec-3-ene-1,5-diyn-7-
ol 22
d
128.6, 128.2, 126.0, 125.0, 96.0, 92.1, 84.2, 82.4, 81.2, 65.5, 62.7, 32.3,
30.6, 28.8, 21.2, 19.6; LRMS (EI, 70 eV) m/z 298 (Mþ), 85 (C5H9Oþ);
HRMS (EI) calcd for C19H22O3 298.1569, found 298.1570.
This material was prepared using the general procedure for the
preparation of acetates: mp 100–103 ꢂC; 1H NMR (500 MHZ, CDCl3)

C.R. Hickenboth et al. / Tetrahedron 64 (2008) 8435–8448
8447
4.3.13. 3-(2-Tetrahydropyranyloxy)-1-[(2-triisopropyl-
silylethynyl)phenyl]-hex-1-ynal 20
m), 5.58 (2H, m), 2.51 (1H, m), 2.39 (1H, m), 2.16 (1H, m), 2.113 (3H,
s), 2.110 (1H, s), 2.05 (1H, m); 13C NMR (125 MHz, CDCl3)
170.15,
d
To a 250 mL 3-neck, round-bottomed flask under Ar was added
THF (30 mL) and diisopropylamine (0.5 mL, 3.5 mmol). This mix-
ture was cooled in a dry ice/acetone bath, then added was a solu-
tion of nBuLi in hexanes (2.1 mL of 1.6 M soln, 3.35 mmol). The
resulting mixture was stirred for 20 min, then a solution of 19
(0.451 g, 1.52 mmol) in THF (5 mL) was added dropwise. After
complete addition the reaction mixture was stirred with cooling for
1 h, then I2 (0.5 g, 1.98 mmol) was added as a solution in THF
(8.5 mL). The resulting solution was stirred with cooling for 1 h,
then at room temperature for 2 h. The reaction was poured onto
satd ammonium chloride (50 mL) and diluted with 10% sodium
bisulfite (50 mL) and Et2O (50 mL). The layers were separated, and
the organic layer was extracted with 2ꢁ50 mL of Et2O. The com-
bined organics were washed with 10% sodium bisulfite (50 mL) and
dried over Na2SO4. Concentration under vacuum yielded an orange
oil (0.636 g, 98%), which darkened with standing. The oil was im-
mediately taken up in CH2Cl2 (85 mL) and placed in a 200 mL round
bottom flask equipped with a magnetic stirrer and rubber stopper.
PDC (5.66 g) was then added, and the resulting solution stirred.
After 12 h of stirring, TLC analysis indicated the complete con-
sumption of starting material (1:1 hexane/EtOAc, Rf¼0.6) the re-
action was filtered through Celite. The Celite plug was washed with
CH2Cl2 (300 mL), then the filtrate was concentrated under vacuum.
The residue was purified by flash chromatography (10:1 hexane/
EtOAc/5:1 hexane/EtOAc, silica) yielding aldehyde 20 (0.421 g,
63%) as an oil, which was used immediately in the next reaction.
170.13, 129.42, 129.40, 128.88, 128.87, 128.37, 128.32, 95.3, 95.2,
86.01, 86.00, 65.0, 64.5, 30.5, 30.3, 21.2; LRMS (EI, 70 eV) m/z 296
(Mþ), 254 ([MꢀC2H2O]þ), 236 ([MꢀAcOH]þ), 212 ([MꢀC4H4O2]þ);
HRMS (EI, 70 eV) calcd for C18H16O4 296.1049, found 296.1037.
4.3.16. 2,20-Azobis{[2-methyl-N-[2-ethyl-(2-methylpropenoate)]]-
propionamide} 26
Prepared according to the general procedure for the preparation
of dimethacrylates. The crude material was placed on a silica plug,
and the plug was washed with 20:1 hexane/EtOAc (60 mL), then
dimethacrylate 26 was eluted with methanol. Concentration of the
methanol filtrate yielded a white solid, which was used without
further purification: 1H NMR (CDCl3, 500 MHz)
6.09 (2H, s), 5.58 (2H, s), 4.30 (4H, t, J¼5.4 Hz), 3.67 (4H, t, J¼5.5 Hz),
1.92 (6H, S), 1.31 (12H, s); 13C NMR (CDCl3, 125 MHz)
174.0, 167.3,
d 7.29 (2H, br s),
d
135.8, 126.1, 74.6, 63.4, 38.7, 22.9, 18.4; HRMS (ESI) calcd for
C
20H33N4O6 [MþH]þ 425.2400, found 425.2398.
4.3.17. 2,20-Azo-2-{[2-methyl-N-[2-ethyl-(2-methylpropenoate)]-
propionamide}-20-[2-methyl-N-(2-ethylacetate)]-propionamide 27
Into a scintillation vial equipped with a magnetic stirrer and
plastic screw cap was added 2,20-azobis[2-methyl-N-(2-hydroxy-
ethyl)propionamide] (0.508 g, 1.76 mmol) and a 4:1 mix of DMF/
pyridine (10 mL). To this solution was added acetic anhydride
(0.25 mL, 2.64 mmol), and the resulting solution was stirred for 5 h,
then the solvent was concentrated under vacuum. The crude mix-
ture was purified by flash chromatography (20:1 EtOAc/MeOH,
silica) yielding the mono protected alcohol (0.215 g, 0.654 mmol,
37%) as a yellow oil. This was immediately converted to metha-
crylate using the general procedure for preparation of dimeth-
acrylates reported above, but only using 3 equiv of methacroyl
chloride instead of 6 equiv. The crude residue was purified by flash
chromatography (1:1 hexane/EtOAc, silica) yielding 27 (0.183 g,
4.3.14. 3,4-Benzocyclodec-3-ene-1,5-diyne-7,10-diol 3
Into a flame-dried sealed tube under argon was added NiCl2
(64 mg, 0.493 mmol), CrCl2 (1.84 g, 14.93 mmol), and dry THF
(82 mL). The resulting suspension was cooled in an ice bath. A so-
lution of aldehyde 20 (0.629 g, 1.49 mmol) in dry THF (33 mL) was
added dropwise over 30 min by syringe pump. After complete ad-
dition, the solution was stirred with cooling for 90 min when TLC
analysis (1:1 hexane/EtOAc) showed complete consumption of
starting material. The reaction was quenched with satd ammonium
chloride (100 mL) and H2O (40 mL), then diluted with Et2O
(100 mL). The layers were separated, and the aqueous layer was
extracted with Et2O (2ꢁ100 mL). The combined organic layers were
washed with brine (100 mL) and dried over Na2SO4. The solvent
was removed under vacuum, yielding a yellow oil. This was taken
up in 1:1 MeOH/CH2Cl2 (6 mL). pTSA monohydrate (14 mg,
0.07 mmol) was then added. The resulting solution was stirred and
monitored by TLC (1:1 hexane/EtOAc). When the starting material
was completely consumed (about 1–2 h) the reaction was poured
onto 5% aqueous NaHCO3 and CH2Cl2 (10 mL each). The layers were
separated, and the aqueous layer was extracted with CH2Cl2
(3ꢁ10 mL). The combined organics were washed with satd aqueous
NaHCO3 (10 mL) and dried over Na2SO4. The solvent was removed
under vacuum and the residue was purified by flash chromatog-
raphy (3:1 hexane/EtOAc/2:3 hexane/EtOAc, silica), yielding 3
(0.124 g, 0.584 mmol, 39%) as an off-white solid and a mixture of
0.462 mmol, 70%) as a white solid: 1H NMR (CDCl3, 500 MHz)
d 7.26
(1H, br s), 7.19 (1H, br s), 6.09 (1H, s), 5.58 (1H, s), 4.30 (2H, t,
J¼5.1 Hz), 4.20 (2H, quintet, J¼5.4 Hz), 3.69 (2H, t, J¼5.2 Hz), 3.63
(2H, q, J¼5.2 Hz), 2.04 (3H, s), 1.92 (3H, s), 1.33 (6H, s), 1.32 (6H, s);
13C NMR (CDCl3, 125 MHz)
d 173.9, 171.2, 167.6, 135.8, 126.1, 74.63,
74.61, 63.3, 63.1, 38.7, 38.5, 22.9, 22.8, 20.7, 18.9; HRMS (ESI) calcd
for C18H31N4O6 [MþH]þ 399.2244, found 399.2251.
4.4. General procedure for DSC analysis of diacetates
Into a DSC pan was added 20–30 mL of a solution of enediyne
diacetate in 1,3-dimethoxybenzene (0.1 mL/mg diacetate). The pan
was sealed and placed in the DSC instrument, and analyzed. A
second scan was examined in all cases, to confirm that the exo-
therm was irreversible.
4.5. Synthesis of PMMA beads46
Benzoyl peroxide and the appropriate crosslinker (1.25:1 mol
ratio) were added to a flask containing MMA and N,N-dimethyl-
aniline (40 mol % versus benzoyl peroxide). After several minutes,
a homogeneous solution was obtained. A second flask was equip-
ped with a magnetic stirrer and rubber stopper and placed under
N2. This was then charged with an aqueous buffer solution of
phosphoric acid (0.1 M, pH¼7) and poly(vinyl alcohol) (0.3 wt %).
The MMA solution was then added to the rapidly stirring aqueous
solution. Then, the stirring rate was adjusted until the appropriate
drop size was obtained. The reaction was stirred overnight, and the
beads were collected by vacuum filtration and dried. The beads
diastereomers: 1H NMR (500 MHz, CD3OD)
m), 4.59 (1H, m), 4.52 (1H, m), 2.38 (1H, m), 2.27 (1H, m), 1.91 (2H,
m); 13C NMR (125 MHz, CD3OD)
128.9, 128.8, 128.61, 128.56,
d 7.36 (2H, m), 7.30 (2H,
d
128.11, 128.10, 99.5. 99.4, 83.7, 83.6, 62.60, 62.56, 33.8, 33.0; LRMS
(EI, 70 eV) m/z 212 (Mþ), 194 ([MꢀH2O]þ), 165, 149; HRMS (EI,
70 eV) calcd for C14H12O2 212.0837, found 212.0834.
4.3.15. 7,10-Diacetoxy-3,4-benzocyclodec-3-ene-1,5-diyne 23
Prepared according to the general procedure for diacetates. The
crude material was purified by flash chromatography (10:1 hexane/
EtOAc, silica) yielding 23 (92%) as a white solid and a mixture of
varied in size from 100–1000
mm in diameter, with 70 wt % of the
diastereomers: 1H NMR (500 MHz, CDCl3)
d
7.40 (2H, m), 7.29 (2H,
beads falling between 500 and 1000 m
m sieves.

8448
C.R. Hickenboth et al. / Tetrahedron 64 (2008) 8435–8448
16. Wiita, A. P.; Perez-Jimenez, R.; Walther, K. A.; Grater, F.; Berne, B. J.; Holmgren,
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4.6. General synthesis for DSC testing of beads
The microspheres containing enediyne crosslinks were taken
into an Ar-filled glove box. Approximately 15 mg of beads were
loaded into DSC pans, along with 15 mL of MMA. The pans were then
sealed and left to swell for 24 h, then removed from the glove box
and analyzed by DSC.
22. Rawat, D. S.; Zaleski, J. M. Synlett 2004, 393.
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This work was supported by grants from the Air Force Office of
Scientific Research and The Petroleum Research Fund, and in part
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