Synthesis of a C1-symmetric Box macrocycle and studies towards active-template synthesis of mechanically planar chiral rotaxanes

Article abstract of DOI:10.1016/j.tet.2012.10.069

A C₁-symmetric Box macrocycle has been synthesized for the first time. The Box macrocycle along with other C₁ and C ₂-symmetric Box ligands were evaluated and compared as ligands in the Cadiot-Chodkiewicz, oxidative Heck and CuAAC 'click' reactions as part of our studies towards achieving active-metal template synthesis of mechanically planar chiral rotaxanes. This study constitutes the first report of Cadiot-Chodkiewicz and CuAAC 'click' reactions using Box ligands, as well as the first dedicated study of oxidative Heck reactions using Box ligands.

Full text of DOI:10.1016/j.tet.2012.10.069

Tetrahedron 69 (2013) 57e68
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of a C1-symmetric Box macrocycle and studies towards
active-template synthesis of mechanically planar chiral rotaxanes
*
Pauline E. Glen, James A.T. O’Neill, Ai-Lan Lee
Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 August 2012
Received in revised form 3 October 2012
Accepted 22 October 2012
Available online 30 October 2012
A C1-symmetric Box macrocycle has been synthesized for the first time. The Box macrocycle along with
other C1 and C2-symmetric Box ligands were evaluated and compared as ligands in the Ca-
dioteChodkiewicz, oxidative Heck and CuAAC ‘click’ reactions as part of our studies towards achieving
active-metal template synthesis of mechanically planar chiral rotaxanes. This study constitutes the first
report of CadioteChodkiewicz and CuAAC ‘click’ reactions using Box ligands, as well as the first dedicated
study of oxidative Heck reactions using Box ligands.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Macrocycles
Bis-oxazolines
Oxidative Heck
CuAAC click
CadioteChodkiewicz
Rotaxane
1. Introduction
an inherently chiral pseudorotaxane, achieving a de of <8%.7 Thus,
the goal of efficientlysynthesizing and investigating the asymmetric
The synthesis of interlocked molecules such as catenanes and
rotaxanes is of great contemporary interest to chemists due not only
to their peculiar structures but also their potential applications in
nanotechnologydfor example, as molecular machines, switches,
wires and motors.1 Additionally, rotaxanes and knots found in na-
ture exhibit remarkable activities compared with linear analogues.2
So far, however, much less attention has beenpaid to one of the most
interesting and yet least exploited features of interlocked architec-
tures: their chiralityda rotaxane can possess mechanical planar
chirality (sometimes referred to as ‘cyclochirality’)3 even if both the
wheel and axle are achiral themselves.3 This inherent chiralityarises
if there is dissymmetry in both the ring and the thread, for example,
if both the axle and the wheel bear groups, which impart di-
rectionality (Fig. 1). Planar chiral rotaxanes have seen application as
chiral sensors for amino acids,4c and other chiral rotaxanes have
shown promise in asymmetric catalysis applications.5 To date,
however, only one attempt at an enantioselective synthesis of
mechanically planar chiral rotaxanes has been reported, yielding an
optically active rotaxane in only 4.4% ee.6 Prior to that, optically
active planar chiral rotaxanes have been isolated by preparative
chiral stationary phase HPLC separation of a racemic mixture.4 In
addition, Lacour et al. attempted the diastereoselective synthesis of
induction properties of planar chiral rotaxanes, especially ones with
no other element of chirality, remains a major challenge.
Fig. 1. Mechanical planar chirality in rotaxanes.
Recently, Leigh and co-workers pioneered the use of the active-
template metal strategy as an efficient way of synthesising inter-
locked molecules.8 The active-metal template strategy utilises the
metal to play a dual role of template for entwining or threading the
components and as a catalyst for covalent bond formation for
capturing the final interlocked product. For rotaxane formation, the
macrocycle thus acts as a ligand to coordinate a metal, which in
turn acts as a catalyst to mediate the covalent bond formation be-
tween two half-threads in the cavity of the macrocycle, leading to
a rotaxane (Scheme 1). The use of a metaleligand complex in such
a way opens the possibility of combining asymmetric catalysis with
rotaxane bond formation.
* Corresponding author. E-mail address: A.Lee@hw.ac.uk (A.-L. Lee).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.069

58
P.E. Glen et al. / Tetrahedron 69 (2013) 57e68
2. Results and discussion
2.1. Synthesis of C1-symmetric Box macrocycle 1
Our first aim was thus to synthesize a suitable C1-symmetric
macrocycle with sterically different faces, which can act as a ligand
for various metal-catalyzed reactions, and whose point chirality
could be removed after the rotaxane forming process. With this in
mind, we chose to synthesize bis-oxazoline (Box) macrocycle 1.9
While examples of C2-symmetric Box macrocycles have been re-
ꢀ
ꢀ
ꢁ
ꢁ
ported by Zinic, Sunjic and co-workers as chiral ligands for Cu-
catalyzed reactions,10 there are no examples of C1-symmetric Box
macrocycles in the literature.11e15 Our retrosynthetic plan involves
ring closing metathesis/hydrogenation of 3 as the key macro-
cyclisation step, followed by cyclisation of 2 to the bis-oxazoline
(Scheme 3). The unsymmetrical fragment 3 will in turn be assem-
bled through successive amide couplings of dimethyl malonic acid
monomethylester 4 with amino alcohols 5 and 6.
Scheme 1. Active-metal template strategy for forming rotaxanes. (a) Metal-catalyzed
covalent bond formation. (b) Metal template turnover in catalytic active-metal tem-
plate synthesis of rotaxanes.
To this end, we were interested in investigating an asymmetric
active-template method to form planar chiral rotaxanes (Scheme 2).
If a cross-coupling reaction of two distinct half-threads is used with
a macrocycle that lacks any element of symmetry (i.e., C1-symmet-
ric), and the faces of the metal macrocycle complex are designed to
be stericallydifferent(e.g., byhaving point chirality), the approach of
the first fragment should be selectively from the less sterically hin-
dered face of the macrocycle. Approach of the second fragment from
the opposite face followed by the metal-catalysed bond formation to
form the [2]rotaxane should lead to an optically active, planar chiral
rotaxane. If the point chirality within the macrocycle is then re-
moved, the resulting rotaxane will be left solely with mechanical
planar chirality.
Scheme 3. Retrosynthetic analysis of macrocycle 1.
Amino alcohol 5 was prepared as outlined in Scheme 4. Esteri-
fication followed by N-protection of 4-hydroxy- -phenylglycine 7
L
furnished 8 in high yield (92%). Reduction of ester 8 with LiAlH4
afforded both alcohol 9 as expected, but also oxazolidinone 10,
resulting from reaction between the alcohol and carbamate pro-
tecting group. As both products 9 and 10 can be taken forward in
the synthetic scheme both were alkylated with 6-bromo-1-hexene
under standard conditions to yield ethers 11 and 12. A mixture of
these ethers was then subjected to basic conditions in order to
attain amino alcohol 5 in excellent yield (95%).
Synthesis of the other amino alcohol portion 6 began with the
alkylation of Boc- -tyrosine methyl ester 13 with 11-
D
Scheme 2. Proposed asymmetric active-metal template for rotaxane formation. (a)
Approach of first fragment to less sterically hindered face of asymmetric macrocycle I.
(b) Approach of second fragment to opposite face. (c) Covalent bond-forming reaction
and demetallation to furnish chiral rotaxane II.
bromoundecene to provide ether 14 in an 83% yield (Scheme 5).
Alcohol 15 was produced by reduction of 14 with LiBH4 (98%).
Subsequent deprotection of the Boc group gave amino alcohol 6 in
almost quantitative yield.
With both amino alcohols in hand, assembly of macrocycle 1
was carried out (Scheme 6). The EDCI-promoted coupling of di-
methyl malonic acid monomethylester 4 with amino alcohol 5
followed by hydrolysis afforded amide 16 in an 84% yield. Coupling
of amino alcohol 6 with 16, in a TBTU-promoted reaction, provided
unsymmetrical diene 3 in a 73% yield. Treatment of diene 3 with
Grubbs’ first generation catalyst under high dilution conditions and
In this article, we present the synthesis of the first C1-sym-
metric Box macrocycle and its application, along with other model
C1- and C2-symmetric Box ligands, in the CadioteChodkiewicz,
oxidative Heck and CuAAC ‘click’ reactions as part of our studies
towards achieving the active-metal template synthesis of chiral
rotaxanes.

P.E. Glen et al. / Tetrahedron 69 (2013) 57e68
59
dichloride 17 in high yield (94%). Cyclisation to the Box macrocycle
1 was then achieved by treatment of 17 with TBAF.16 At this point,
we discovered that the Box macrocycle 1 is unstable to silica gel
chromatography, forming decomposition products as well as
reverting to the uncyclised 2. Eventually, alumina chromatography
techniques were developed for successful purification of 1. Thus,
the synthesis of the first C1-symmetric bis-oxazoline macrocycle 1
was achieved in a gram scale.
2.2. Catalysis studies
Following the successful synthesis of macrocycle 1, we set out to
study the applicability of Box ligands in the CadioteChodkiewicz,17
oxidative Heck18 and CuAAC ‘click’19 reactions as these reactions
have been shown to perform well in the active-template synthesis
of rotaxanes, and are suitable for heterocoupling of two different
half-threads, required to form a dissymmetric thread.20e22,23
However, since only pyridine and/or bipyridine-based macro-
cycles have been utilized in these rotaxane forming reactions, and
Box ligands have either not been evaluated (CadioteChodkiewicz,
CuAAC) or have only seen limited study (oxidative Heck),24 it was
necessary for us to carry out model studies in order to understand
how bis-oxazoline ligands will perform for these reactions. Thus,
non-macrocyclic C2-Box ligands 18 and 19, model C1-Box ligand 20
as well as macrocycle 1 were utilized in these investigations for
comparison purposes between macrocyclic/non-macrocyclic/C1/C2
ligands.
Scheme 4. Synthesis of amino alcohol 5.
In order to emphasize the asymmetry of any planar chiral
rotaxanes produced, half-threads with significantly different
stopper groups were utilized in our studies. In the Cu(I)-catalysed
CadioteChodkiewicz alkyne cross-coupling reaction, stopper
fragments 21 and 22 were employed. When the reaction was
carried out with C2-Box ligand 18 (Table 1, entry 1), hetero-
coupled thread 23 was obtained, along with homocoupled
product 24 in a 74:26 ratio and with a 74% conversion from
bromoalkyne 22. With this encouraging result in hand, efforts
were made to improve the conversion of the reaction. Running
the reaction for 5 days and changing the Cu(I) source to CuCl
allowed for full conversion of bromoalkyne 22 to threads 23 and
24 without a change in the heterocoupled:homocoupled thread
ratio (Table 1, entry 2).
Scheme 5. Synthesis of amino alcohol 6.
Once we had our optimised conditions for the reaction using
C2-Box ligand 18, we turned our attention to model C1-Box ligand
20 and C1-macrocycle 1 (Table 1, entries 3 and 4). To our surprise,
neither of the reactions gave any indication of either hetero-
coupled thread 23 or homocoupled bromide 24. As a control re-
action run in the absence of any ligand (Table 1, entry 5) gives us
a conversion to heterocoupled thread 23 of 34%, it would appear
that the non-macrocycle C1-Box ligand 20 and C1-macrocycle 1
are actually inhibiting the reaction. This is in direct contrast with
C2-Box ligand 18, which promotes the reaction to complete
conversion. There are two possible causes for this outcome. Ei-
ther the benzyl (vs Ph) group is inhibiting the reaction or the
steric hindrance of having both groups on the same face of the
ligand is too great for the reaction to occur. To ascertain the cause,
the reaction was carried out with commercially available C2-
symmetric dibenzyl Box ligand 19 (Table 1, entry 6). The conver-
sion of bromoalkyne 22 to thread 23 was significantly lower for
the dibenzyl Box ligand 19 than for the diphenyl Box compound
18 (22% vs 100%) and was also lower than for the ligand-free
reaction (22% vs 34%). This would imply that the dibenzyl Box
ligand 19 actively inhibits the CadioteChodkiewicz reaction. It
would appear, therefore, that the presence of a benzyl group in
conjunction with the C1-nature of the ligand, with its steric
crowding of one face of the compound, completely prevents the
Scheme 6. Synthesis of macrocycle 1.
subsequent reduction of the alkene with Pd/C under a hydrogen
atmosphere furnished macrocycle 2 in a good 65% yield over two
steps. Finally, Box macrocycle 1 was synthesized from bis-amide 2
in two steps. Reaction of diol 2 with thionyl chloride gave

60
P.E. Glen et al. / Tetrahedron 69 (2013) 57e68
Table 1
Table 2
Optimization studies for the CadioteChodkiewicz reaction
Optimization studies for the oxidative Heck reaction
Conv. of 25 to 27b (%)
DMF/CHCl3 100
DMF/CHCl3 59
DMF/CHCl3 100
a
Entry Box Pd(OAc)2 (%) Oxidant Solvent
1
2
3
4
5
6
7
8
9
10
18
20
20
d
1
20
20
20
20
20
100
100
20
20
20
BQ
BQ
BQ/O2
BQ/O2
BQ/O2
d
DMF/CHCl3
DMF/CHCl3
DMF/CHCl3
DMF/CHCl3
CHCl3
24
21
50c
47
31
20
5
1
d
d
20
1
BQ/O2
BQ/O2
BQ/O2
BQ/O2
Entry
Cu(I)
Box
Time
Conv. of 22 to 23þ24a (%)
Ratio 23/24a
1
2
3
4
5
6
CuI
18
18
20
1
24 h
74
100
0
0
34
22
74:26
74:26
d
CHCl3
CHCl3
CuCl
CuCl
CuCl
CuCl
CuCl
5 days
5 days
5 days
5 days
5 days
d
BQ¼benzoquinone.
a
d
100:0
100:0
With respect to alkene 25.
b
Determined by 1H NMR spectroscopic analysis of the reaction mixture.
19
c
No evidence of rotaxane 28 by mass spectrometry.
a
Determined by 1H NMR spectroscopic analysis of the reaction mixture.
CadioteChodkiewicz reaction from occurring in the presence of
Box ligand 20 and macrocycle 1.
Suspecting competition between the macrocycle 1 and DMF in
ligating to the palladium catalyst, the reaction was repeated in
chloroform alone as this has a lower binding affinity to transition
metals than DMF.25 A ligand-free control reaction indicated that
chloroform was a suitable solvent for the oxidative Heck reaction
between alkene 25 and boronic acid 26, achieving a better con-
version than the ligand-free control in DMF/CHCl3, though still
quite low at 31% (Table 2, entry 8). When the reaction was carried
out with non-macrocyclic C1-Box ligand 20 and macrocycle 1 (Table
2, entries 9 and 10) the conversions were lower than those obtained
in the control reaction; 20% and 5%, respectively. It is apparent from
these results that both the non-macrocyclic Box ligand 20 and
macrocycle 1 are ligated to the metal catalyst throughout the re-
action and are slowing down the reaction compared to the ligand-
free control. This supports our conjecture that the DMF is com-
peting with the Box macrocycle in ligating with the palladium. It
would appear from our results that there is a series in binding af-
finity to palladium between the solvent and Box ligands, which
runs as follows: non-macrocyclic C2-Box 18wnon-macrocyclic C1-
Box 20<DMF<Box macrocycle 1.
With the failure to form rotaxane 28, we turned to investigate
the third known active-metal template reaction for compatibility
with Box ligands: the CuAAC ‘click’ reaction of an azide with an
acetylene. The reaction is known to work well with bipyridine
macrocycles19 but there are no known examples for the use of bis-
oxazoline ligands.
Pleasingly, complete reaction of acetylene 29 with azide 30 was
observed at 80 ꢀC20b to form triazole thread 31 using model C1-Box
ligand 20 (Table 3, entry 1). Substituting 20 with our macrocycle 1
under the same conditions also resulted in full conversion of acet-
ylene 29, but disappointingly there was no evidence of rotaxane 32
in either 1H NMR spectroscopyor mass spectrometry. We speculated
that the macrocycle may no longer be bound to the copper species at
the high temperatures used in the reaction (80 ꢀC). We therefore
decided to optimise the CuAAC reaction at room temperature. Un-
fortunately, initial attempts to optimise the reaction proved irre-
producible. The unreliability of the reaction turned out to be related
to the concentration, which was subject to change through evapo-
ration of the DCM solvent over the long period of the reaction. The
Our investigation into the compatibility of Box ligands in re-
actions known for active-metal template synthesis of rotaxanes
continued with the study into Pd(II) oxidative Heck reactions. Re-
ports of bis-oxazolines as ligands for oxidative Heck reactions are
limited to only a couple of rare examples as part of ligand screens,23
so once again, model studies had to be carried out.
Alkene 25 and boronic acid 26 were employed in the oxidative
Heck reactions to synthesise 27 as the unsymmetrical thread
(Table 2). To our delight, complete conversion of alkene stopper
fragment 25 to thread 27 was obtained when the reaction was
carried out with benzoquinone as the oxidant in 1:1 DMF/CHCl3, as
the components of the reaction were not soluble in DMF alone
(Table 2, entry 1). When the ligand was changed from C2-Box ligand
18 to C1-Box ligand 20 a lower than expected conversion of 59% was
obtained (Table 2, entry 2). However, running the reaction under an
oxygen atmosphere (Table 2, entry 3) successfully promotes com-
plete conversion to thread 27. Comparison with a ligand-free con-
trol reaction (Table 2, entry 4) confirms that the non-macrocyclic
Box ligands 18 and 20 accelerate the reaction under these
conditions.
Encouraged by the complete conversion of alkene 25 to thread
27 by the non-macrocyclic C1-Box ligand 20, the synthesis of
rotaxane 28 was attempted. However, a conversion to non-
interlocked thread 27 of only 21% was achieved (Table 2, entry
5), similar to that of the ligand-free reaction (Table 2, entry 4). It is
also in the region of what would be expected if the palladium
catalyst was not turning over in the reaction (20%). Therefore, the
reaction was repeated with stoichiometric amounts of Pd(OAc)2 in
order to determine if the macrocycle was sequestering the palla-
dium and preventing turnover (Table 2, entry 6). The conversion of
alkene 25 to non-interlocked thread 27 achieved under these
conditions was only 50%, similar to the conversion obtained from
the ligand-free stoichiometric control reaction (Table 2, entry 7,
47%). This similarity, when coupled with the lack of rotaxane 28 in
the reaction, implies that the Box macrocycle 1 is not bound to the
palladium throughout the reaction and only the background re-
action is being observed.

P.E. Glen et al. / Tetrahedron 69 (2013) 57e68
61
reactions were therefore carried out in a sealed vial instead, which
proves that concentration is key to the observing reactivity (Table 3,
entries 3 and 4). Complete conversion of acetylene 29 to thread 31
was achieved in only 48 h through further concentration of the re-
action mixture and with the use of additional azide 30 as this was
found to be a limiting factor (Table 3, entry 5).
ligands 20 and 1 surprisingly inhibit the reaction. Pd(II)-catalysed
oxidative Heck reaction with Box macrocycle 1 succeeds in forming
the coupled thread 27, but not the rotaxane 28. Our investigations
suggest that DMF competes with Box macrocycle 1 as a ligand for Pd
under oxidative Heck conditions. The CuAAC reaction with Box li-
gands 20 and 1 once again successfully forms the non-interlocked
thread 31 under mild conditions, but the desired rotaxane was
formed in only trace quantities. Control studies suggest that the
macrocycle ligand 1 is bound to the metal during the CuAAC reaction,
making it the most promising reaction of the three investigated, al-
though a more rigid macrocycle design is probably necessary for
successful rotaxane formation in the future. Although macrocycle 1
proved unsuitable for our ultimate aim of synthesizing mechanically
planar chiral rotaxanes, the results of our model studies nevertheless
providevaluableinsightintothebehaviourofC1 andC2 bis-oxazolines
as ligands in these copper- and palladium-catalyzed reactions.
Table 3
Optimization studies for CuAAC click reaction
4. Experimental
Entry
Box
Temp (ꢀC)
Concna (mM)
Time
Conv. of 29
to 31b (%)
4.1. General experimental section
1
2
3
4
20
1
20
20
20
1
80c
80c
25
25
25
25
25
10
10
10
68 h
72 h
7 days
4 days
48 h
100
100d
0
Unless otherwise stated, all reactions were performed under
nitrogen atmosphere. 1H NMR spectra were recorded on Bruker
AC200, AV 300, DPX 400 and AV 400 spectrometers at 200, 300 and
400 MHz, respectively, and referenced to residual solvent. 13C NMR
spectra were recorded using the same spectrometers at 50, 75 and
60
40
5e
6e
7e
400
400
400
100
100f
100
48 h
19 h
d
101 MHz, respectively. Chemical shifts (d in parts per million) were
a
With respect to Box.
referenced to tetramethylsilane (TMS) or to residual solvent peaks. J
values are given in Hertz and s, d, dd, dt, ddt, t, tdd, quin. and m
abbreviations correspond to singlet, doublet, doublet of doublet,
doublet of triplet, doublet of doublet of triplet, triplet, triplet of
doublet of doublet, quintet and multiplet. The numbers for the peak
assignment of macrocycle 1 are referred to the system in Scheme 6.
Mass spectra were obtained at the EPSRC National Mass Spec-
trometry Service Centre in Swansea. Infrared spectra were obtained
on PerkineElmer Spectrum 100 FT-IR Universal ATR Sampling Ac-
cessory, deposited neat or as a chloroform solution onto a diamond/
ZnSe plate. Optical rotations were recorded on a Bellingham &
Stanley ADP410 polarimeter. Starting compounds 3-ethoxy-2,2-
dimethyl-3-oxopropanoic acid 4,26 4,40,400-((4-(pent-4-ynyloxy)
phenyl)methanetriyl)tris(tert-butyl benzene) 21,27 4-(3-(4-(tris(4-
tert-butyl-phenyl)methyl)phenoxy) propoxy)phenylboronic acid
26,21 1-(3-azido-propoxy)-4-(tris-(4-tert-butyl-phenyl)-methyl)-
benzene 3022a and (S)-3-(2-hydroxy-1-phenylethylamino)-2,2-
dimethyl-3-oxopropanoic acid 3311d were synthesized according
to literature procedures. All other reagents used were purchased
from commercial suppliers and were used without any further
purification unless otherwise stated. N-Bromosuccinimide (NBS)
was recrystallised from water. Dichloromethane (DCM) was dis-
b
c
d
e
f
Determined by 1H NMR spectroscopic analysis of the reaction mixture.
Reaction carried out in a sealed vessel.
No evidence of rotaxane 32 by mass spectrometry.
With 1.5 equiv azide 30.
Trace amounts of rotaxane 32 detected by mass spectrometry.
Finally, rotaxane synthesis using macrocycle 1 was attempted
again, using the optimised RT conditions and full conversion of
acetylene 29 was achieved (Table 3, entry 6). Regrettably, however,
rotaxane 32 remained elusive; although detected by mass spec-
trometry, it was present in only trace amounts. The most likely
explanation for the lack of rotaxane, that the Box ligands are not in
fact bound to the metal throughout the reaction, is refuted by the
result of the ligand-free control reaction (Table 3, entry 7). Like
Leigh and co-workers,22b we found that the ligand-free reaction
reached complete conversion of acetylene 29 into non-interlocked
thread 31 in only 19 h, compared to the 48 h required for the re-
actions with the bis-oxazoline ligands. The Box ligands must inhibit
the reaction in some fashion, possibly, as postulated by Leigh
et al.,22b by preventing a faster, ligand-free pathway for the re-
action. The lack of rotaxane in our CuAAC ‘click’ reaction with
macrocycle 1 must therefore be due to some hindrance in carrying
out the reaction through the macrocycle cavity, with only a small
percentage of the thread being formed within the cavity. Redesign
of the Box macrocycle 1 to provide a more rigid structure may be
necessary for the successful asymmetric synthesis of planar chiral
rotaxanes via the active-template method.
ꢂ
tilled over CaH2 and stored over 4 A molecular sieves. Acetone was
ꢂ
stored over 3 A sieves. Tetrahydrofuran (THF) was dried by distil-
lation from sodium-benzophenone under nitrogen. Anhydrous N,N
dimethylformamide (DMF) was used as supplied (SuresealÒ). Petrol
ether refers to petroleum ether (40e60). All glassware was heat
gun dried. Flash column chromatography, unless otherwise stated,
was carried out using Matrix silica gel 60 from Fisher Chemicals.
Alumina flash column chromatography was carried out using ac-
tivated neutral aluminium oxide Brockmann I 150 mesh from
Aldrich. TLC was performed using Merck silica gel 60 F254 pre-
coated sheets and visualized by UV (254 nm) or stained by the
use of aqueous acidic KMnO4 or aqueous acidic ammonium mo-
lybdate as appropriate.
3. Conclusions
Thesynthesis of the first C1-symmetricbis-oxazolinemacrocycle 1
was successfully achieved in gram scale. Macrocycle 1, along with
model C2 bis-oxazoline ligands 18 and 19, and C1-Box ligand 20 were
investigated as ligands for the CadioteChodkiewicz, oxidative Heck
and CuAAC ‘click’ reactions. This study constitutes the first report of
CadioteChodkiewicz and CuAAC ‘click’ reactions using Box ligands, as
well as the first dedicated study of oxidative Heck reactions using Box
ligands. In the CadioteChodkiewicz reaction, C2-Box ligand 18 suc-
cessfully promotes the reaction to completion, but in contrast, C1-Box
4.1.1. (S)-Methyl 2-(4-hydroxyphenyl)-2-(methoxycarbonylamino)
acetate (8). Thionyl chloride (41.0 mL, 560 mmol) was added
dropwise to a stirring solution of (S)-2-amino-2-(4-hydroxyphenyl)

62
P.E. Glen et al. / Tetrahedron 69 (2013) 57e68
acetic acid 7 (52.5 g, 310 mmol) in methanol (1.1 L). The resulting
mixture was stirred at 25 ꢀC for 16 h. The reaction was concentrated
under reduced pressure and the resulting residue washed with
diethyl ether. The resulting crude product was dissolved in 1:1 THF/
H2O (1 L) and NaHCO3 (79 g, 940 mmol) added. Methyl chlor-
oformate (26.6 mL, 340 mmol) was added dropwise and the
resulting mixture stirred at 25 ꢀC for 16 h. The reaction was
quenched with water (500 mL) and the aqueous layer extracted
with ethyl acetate. The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. The resulting
residue was recrystallised from ethyl acetate/hexane to yield the
title compound 8 (68.8 g, 92%) as a white solid. Mp 138e139 ꢀC; Rf
heated at reflux for 43 h. After cooling, the reaction was quenched
with water (80 mL) and the aqueous layer extracted with ethyl ac-
etate. The combined organic layers were washed with water, brine,
dried (MgSO4) and concentrated under reduced pressure. The
resulting residue was purified by column chromatography (1:1 ethyl
acetate/petrol ether to 9:1 ethyl acetate/petrol ether) to yield the title
compound 11 (6.94 g, 68%) as a white solid. Mp 73e74 ꢀC; Rf 0.48 (4:1
ethyl acetate/petrol ether); ½a D20
ꢁ
þ64.0 (c 1.00, CHCl3); nmax/cmꢂ1
3337 br (OH, NH), 2945 (CH), 2867 (CH), 1692 (C]O), 1641 (C]C),
1613 (Ar C]C), 1586 (Ar C]C), 1533 (NH), 1513 (Ar C]C), 1478 (Ar
C]C), 1460 (OH), 1265 (NeCOeO), 1241 br (CeOeC), 1178 (Ar CH),
1114 (CeOeC), 1089 (CeO), 1056 (NeCOeO), 1030 (CeOH), 997 (]
CH), 915 (]CH), 825 (Ar CH), 779 (OH); dH (200 MHz, CDCl3)
7.25e7.16 (2H, m, AreH), 6.96e6.72 (2H, m, AreH), 5.83 (1H, ddt, J
17.0, 10.4, 6.6, CH]CH2), 5.37 (1H, d, J 7.1, NH), 5.11e4.92 (2H, m, ]
CH2), 4.77 (1H, dd, J 7.1, 5.4, CHCH2OH), 3.95 (2H, t, J 6.2, OCH2), 3.84
(2H, t, J 5.4, CHCH2OH), 3.68 (3H, s, OCH3), 2.31e2.04 (3H, m, alkyl-H,
OH), 1.90e1.69 (2H, m, alkyl-H), 1.68e1.46 (2H, m, alkyl-H); dC
(50 MHz, CDCl3) 158.8 (C), 157.1 (C), 138.5 (CH), 130.9 (C), 127.7 (CH),
114.8 (CH and CH2 overlapping), 67.8 (CH2), 66.6 (CH2), 56.6 (CH),
52.4 (CH3), 33.4 (CH2), 28.6 (CH2), 25.3 (CH2); HRMS (ESI) [MþH]þ
calcd for C16H24NO4 294.1700, found 294.1703.
0.29 (1:1 ethyl acetate/petrol ether); ½a D21
þ153.5 (c 0.99, MeOH);
ꢁ
nmax/cmꢂ1 3371 (NH), 3279 br (OH), 3000 (CH), 2951 (CH), 2845
(CH), 1756 (C]O), 1698 (C]O), 1616 (Ar C]C), 1598 (Ar C]C), 1510
(Ar C]C), 1440 (Ar C]C), 1264 (NeCOeO), 1213 (CeOH), 1171 (Ar
CH), 1059 (NeCOeO), 1011 (CeOH), 780 (Ar CH); dH (200 MHz,
C2D6SO) 8.00 (1H, d, J 7.5, NH), 7.29e7.04 (2H, m, AreH), 6.79e6.60
(2H, m, AreH), 5.08 (1H, d, J 7.5, CHCOOMe), 3.60 (3H, s, OCH3), 3.55
(3H, s, OCH3); dC (50 MHz, C2D6SO) 171.8 (C), 157.4 (C), 156.5 (C),
129.1 (CH), 126.4 (C), 115.3 (CH), 57.5 (CH), 52.1 (CH3), 51.6 (CH3);
HRMS (ESI) [MþH]þ calcd for C11H14NO5 240.0866, found 240.0869.
Cyclic compound 12 was also formed as a side-product (2.83 g,
4.1.2. (S)-Methyl
2-hydroxy-1-(4-hydroxyphenyl)ethylcarbamate
32%) as a white solid. Mp 96e97 ꢀC; Rf 0.68 (2:1 ethyl acetate/petrol
(9). LiAlH4 (7.60 g, 200 mmol) was added portionwise to a stirring
solution of (S)-methyl 2-(4-hydroxyphenyl)-2-((methoxycarbonyl)
amino)acetate 8 (24.0 g, 100 mmol) in THF (1.5 L) at 0 ꢀC. The resulting
mixture was stirred at 0 ꢀC for 1 h then warmed to RT over 24 h. The
reaction was cooled to 0 ꢀC and ice-cold water (16 mL) added. The
mixture was stirred at 0 ꢀC for 10 min then 15% aq NaOH (16 mL) was
added and the reaction stirred at 0 ꢀC for a further 10 min. Ice-cold
water (48 mL) was added and the reaction stirred at 0 ꢀC for
30 min. The resulting suspension was filtered and the filtrate dried
(MgSO4) then concentrated under reduced pressure. The resulting
residue was purified by column chromatography (petrol ether to 1:1
petrol ether/ethyl acetate to ethyl acetate) to yield the title compound
9 (12.7 g, 60%) as a white solid. Mp 112e115 ꢀC; Rf 0.20 (2:1 ethyl
ether); ½a 2D2
ꢁ
þ28.6 (c 0.14, CHCl3); nmax/cmꢂ1 3233 (NH), 3139 (Ar
CH), 2936 (CH), 2921 (CH), 1740 (C]O), 1640 (Ar C]C), 1614 (NH),
1586 (Ar C]C), 1512 (Ar C]C), 1393 (]CH), 1239 (CeO), 1061
(CeO), 1025 (NeCOeO), 925 (]CH), 828 (Ar CH); dH (200 MHz,
CDCl3) 7.33e7.21 (2H, m, AreH), 6.98e6.85 (2H, m, AreH), 5.84 (1H,
ddt, J 17.0, 10.0, 6.6, CH]CH2), 5.50 (1H, s, NH), 5.14e4.84 (3H, m,
CHCHHO, ]CH2), 4.67 (1H, dd, J 8.3, 8.3, CHCHHO), 4.17 (1H, dd, J
8.3, 7.1, CHCH2O), 3.97 (2H, t, J 6.4, OCH2CH2), 2.16e2.04 (2H, m,
alkyl-H), 1.90e1.72 (2H, m, alkyl-H), 1.61e1.48 (2H, m, alkyl-H); dC
(50 MHz, CDCl3) 159.5 (C), 138.4 (C), 131.0 (C), 127.4 (2ꢃCH over-
lapping), 115.0 (CH), 114.8 (CH2), 72.7 (CH2), 67.9 (CH2), 55.9 (CH),
33.4 (CH2), 28.6 (CH2), 25.2 (CH2); HRMS (ESI) [MþH]þ calcd for
C15H20NO3 262.1438, found 262.1441.
acetate/petrol ether); ½a D18
ꢁ
þ70.6 (c 1.02, MeOH); nmax/cmꢂ1 3339
(OH/NH), 2944 (CH), 1685 (C]O), 1600 (NH), 1534 (Ar C]C), 1517 (Ar
C]C), 1452 (Ar C]C), 1360 (OH), 1218 (Ar CeO), 1173 (NeCOeO),
1058 (NeCOeO), 1013 (CeO); dH (300 MHz, C2D6SO) 7.40 (1H, d, J 8.1,
NH), 7.13e7.03 (2H, m, AreH), 6.78e6.53 (2H, m, AreH), 4.75 (1H, t, J
5.5, OH), 4.46 (1H, dt, J 8.1, 6.2, CHCH2OH), 3.50 (3H, s, OCH3), 3.44 (2H,
t, J 6.2, CHCH2OH); dC (75 MHz, C2D6SO) 156.8 (C), 156.7 (C), 132.1 (C),
128.3 (CH), 115.2 (CH), 65.3 (CH2), 57.0 (CH), 51.6 (CH3); HRMS (ESI)
[MþH]þ calcd for C10H14NO4 212.0917, found 212.0919.
4.1.5. (S)-2-Amino-2-(4-(hex-5-enyloxy)phenyl)ethanol (5). A sus-
pension
of
(S)-methyl
1-(4-(hex-5-enyloxy)phenyl)-2-
hydroxyethylcarbamate 11 (8.71 g, 29.7 mmol) and (S)-4-(4-(hex-
5-enyloxy)phenyl)oxazolidin-2-one 12 (2.86 g, 10.9 mmol) in a so-
lution of KOH (25% aq, 365 mL) was stirred at 50 ꢀC for 27 h. After
cooling, the reaction was quenched with water (365 mL) and
extracted with ethyl acetate. The combined organic layers were
washed with water, brine, dried (MgSO4) and concentrated under
reduced pressure to yield the title compound 5 (9.12 g, 95%) as
a pale yellow solid. Mp 72e73 ꢀC; Rf 0.03 (20:1 DCM/methanol);
4.1.3. (S)-4-(4-Hydroxyphenyl)oxazolidin-2-one (10).28 Compound
10 was also formed as a side-product (5.40 g, 30%) as a white solid.
Mp 203e205 ꢀC [lit.28 mp 201e204 ꢀC]; Rf 0.32 (4:1 ethyl acetate/
½
a 2D0
ꢁ
þ28.3 (c 1.27, CHCl3); nmax/cmꢂ1 3500 br (OH), 3323 (NH),
3067 (Ar CH), 2936 (CH), 2865 (CH), 1713 (Ar CeH), 1642 br (C]C,
NH2), 1611 (Ar C]C), 1559 (Ar C]C), 1512 (Ar C]C), 1469 (Ar C]C),
1389 (CeN), 1245 (CeOeC), 1176 (CeN), 1155 (CeN), 1065 (Ar CH),
1028 (CeOH), 993 (]CH), 907 (]CH), 827 (Ar CH, NH2), 809 (NH2);
dH (200 MHz, CDCl3) 7.26e7.19 (2H, m, AreH), 6.97e6.70 (2H, m,
AreH), 6.00e5.68 (1H, m, CH]CH2), 5.14e4.84 (2H, m, ]CH2),
4.09e3.84 (3H, m, OCH2, CHCH2O), 3.69 (1H, dd, J 10.8, 4.6,
CHCHHOH), 3.52 (1H, dd, J 10.8, 8.3, CHCHHOH), 2.40 (3H, s, NH2,
OH), 2.22e2.00 (2H, m, alkyl-H), 1.91e1.69 (2H, m, alkyl-H),
1.68e1.39 (2H, m, alkyl-H); dC (50 MHz, CDCl3) 158.4 (C), 138.5 (CH),
134.4 (C), 127.5 (CH), 114.7 (CH), 114.5 (CH2), 67.9 (CH2), 67.7 (CH2),
56.7 (CH), 33.4 (CH2), 28.6 (CH2), 25.2 (CH2); HRMS (ESI) [MþNa]þ
calcd for C14H21NNaO2 258.1465, found 258.1467.
petrol ether); ½a D20
ꢁ
þ48.6 (c 1.48, MeOH) [lit.28
½
a 2D0
ꢁ
þ41.4 (c 1.70,
EtOH)]; nmax/cmꢂ1 3304 (NH), 3226 br (OH), 2925 (CH), 2833 (CH),
1724 (C]O), 1614 (Ar C]C), 1601 (NH), 1513 (Ar C]C), 1487 (Ar C]
C), 1374 (OH), 1238 (NeCOeO), 1212 (CeO), 1029 (NeCOeO), 825
(Ar CH); dH (300 MHz, C2D6SO) 8.04 (1H, s, NH), 7.19e7.09 (2H, m,
AreH), 6.82e6.72 (2H, m, AreH), 4.81 (1H, dd, J 8.6, 7.0, CHCHHO),
4.60 (1H, dd, J 8.6, 8.6, CHCHHO), 3.95 (1H, dd, J 8.6, 7.0, CHCHHO);
dC (75 MHz, C2D6SO) 158.9 (C), 157.2 (C), 131.0 (C), 127.4 (CH), 115.4
(CH), 71.6 (CH2), 54.8 (CH); HRMS (ESI) [MþH]þ calcd for C9H10NO3
180.0655, found 180.0654.
4.1.4. (S)-Methyl 1-(4-(hex-5-enyloxy)phenyl)-2-hydroxyethyl carba-
mate (11). 6-Bromohex-1-ene (5.00 mL, 37.7 mmol) was added
dropwise to a stirring suspension of (S)-methyl 2-hydroxy-1-(4-
hydroxyphenyl)ethylcarbamate 9 (7.42 g, 35.1 mmol) and K2CO3
(5.36 g, 38.8 mmol) in acetone (80 mL). The resulting mixture was
4.1.6. (R)-Methyl 2-(tert-butoxycarbonylamino)-3-(4-(undec-10-
enyloxy)phenyl)propanoate (14). A solution of 11-bromoundec-1-
ene (53.4 g, 230 mmol) in acetonitrile (100 mL) was added

P.E. Glen et al. / Tetrahedron 69 (2013) 57e68
63
dropwise to a stirring suspension of (R)-methyl 2-((tert-butox-
ycarbonyl)amino)-3-(4-hydroxyphenyl)propanoate 13 (56.4 g,
190 mmol) and K2CO3 (32.0 g, 230 mmol) in acetonitrile (250 mL).
The resulting mixture was heated at reflux for 18 h. After cooling,
the reaction was quenched with water (500 mL) and the aqueous
layer extracted with ethyl acetate. The combined organic layers
were washed with brine, dried (Na2SO4) and concentrated under
reduced pressure. The resulting residue was purified by column
chromatography (petrol ether to 4:1 petrol ether/ethyl acetate)
then recrystallised from toluene/petrol ether to yield the title
compound 14 (70.8 g, 83%) as a white solid. Mp 59e62 ꢀC; Rf 0.30
washed with brine, dried (MgSO4) and concentrated under reduced
pressure to yield the title compound 6 (44.7 g, 99%) as a white solid.
Mp 75e78 ꢀC; Rf 0.03 (9:1 petrol ether/ethyl acetate); ½a 2D0
þ7.7
ꢁ
(c 1.04, CHCl3); nmax/cmꢂ1 3355 (NH), 3298 (NH), 3077 (Ar CH), 2923
br (OH), 2851 (CH), 1613 (Ar C]C), 1582 (Ar C]C), 1509 (Ar C]C),
1467 (Ar C]C), 1243 (CeOeC), 1059 (CeOH), 909 (]CH); dH
(400 MHz, CDCl3) 7.13e7.03 (2H, m, AreH), 6.90e6.79 (2H, m, AreH),
5.82 (1H, ddt, J 17.0, 10.3, 6.7, CH]CH2), 5.06e4.88 (2H, m, ]CH2),
3.93 (2H, t, J 6.5, OCH2), 3.63 (1H, dd, J 10.6, 3.2, CHHOH), 3.37 (1H, dd,
J 10.6, 6.5, CHHOH), 3.13e3.02 (1H, m, CHNH2), 2.73 (1H, dd, J 13.5,
5.3, CHHCHNH2), 2.47 (1H, dd, J 13.5, 8.5, CHHCHNH2), 2.24e1.99 (5H,
m, alkyl-H, NH2, OH), 1.85e1.70 (2H, m, alkyl-H), 1.51e1.23 (12H, m,
alkyl-H); dC (101 MHz, CDCl3) 157.8 (C), 139.2 (CH), 130.3 (CH), 130.1
(C), 114.6 (CH), 114.1 (CH2), 68.0 (CH2), 66.1 (CH2), 54.3 (CH), 39.8
(CH2), 33.8 (CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 29.1 (CH2) (plus
one overlapping peak), 27.6 (CH2), 26.0 (CH2); HRMS (ESI) [MþH]þ
calcd for C20H34NO2 320.2584, found 320.2588.
(9:1 petrol ether/ethyl acetate); ½a D20
ꢁ
ꢂ33.9 (c 1.12, CHCl3); nmax
/
cmꢂ1 3367 (NH), 2980 (Ar CH), 2920 (CH), 2851 (CH), 1737 (C]O),
1691 (C]O), 1641 (C]C), 1614 (Ar C]C), 1583 (NH), 1524 (Ar C]C),
1512 (Ar C]C), 1467 (CH), 1367 (CH), 1242 (CeOeC), 1161 (CeOeC/
NeCOeO) 994 (]CH), 909 (]CH), 826 (Ar CH); dH (300 MHz,
CDCl3) 7.08e6.99 (2H, m, AreH), 6.89e6.77 (2H, m, AreH), 5.82
(1H, ddt, J 16.9, 10.3, 6.6, CH]CH2), 5.06e4.90 (3H, m, ]CH2, NH),
4.61e4.46 (1H, m, CHCOOMe), 3.93 (2H, t, J 6.6, OCH2), 3.72 (3H, s,
OCH3), 3.11e2.92 (2H, m, CH2CHCO), 2.11e1.98 (2H, m, alkyl-H),
1.84e1.68 (2H, m, alkyl-H), 1.51e1.25 (21H, m, alkyl-H, C(CH3)3); dC
(75 MHz, CDCl3) 172.4 (C), 158.2 (C), 154.9 (C), 139.2 (CH), 130.2
(CH),127.7 (C),114.5 (CH),114.1 (CH2), 79.9 (C), 68.0 (CH2), 54.5 (CH),
52.2 (CH3), 37.5 (CH2), 33.8 (CH2), 29.5 (CH2), 29.4 (CH2), 29.1 (CH2),
28.9 (CH2) (plus two overlapping peaks), 28.3 (CH3), 26.0 (CH2);
HRMS (ESI) [MþH]þ calcd for C26H42NO5 448.3057, found
448.3053.
4.1.9. (S)-Ethyl 3-(1-(4-(hex-5-enyloxy)phenyl)-2-hydroxyethy lam-
ino)-2,2-dimethyl-3-oxopropanoate (34). A solution of EDCI (9.50 g,
50.0 mmol) in chloroform (53 mL) was added dropwise to a stirring
solution of (S)-2-amino-(4-(hex-5-enyloxy)phenyl)ethanol
5
(12.0 g, 50.0 mmol) and HOBt (6.70 g, 50.0 mmol) in chloroform
(395 mL) at 0 ꢀC. The resulting mixture was stirred at 0 ꢀC for 1.5 h.
A solution of 3-ethoxy-2,2-dimethyl-3-oxopropanoic acid 4 (8.50 g,
45.0 mmol) in chloroform (79 mL) was added dropwise. The
resulting mixture was allowed to warm to RT for 18 h. The reaction
was quenched with 3 M aq HCl (100 mL) and the aqueous layer
extracted with chloroform. The combined organic layers were
washed with water, dried (Na2SO4) and concentrated under re-
duced pressure. The resulting residue was purified by column
chromatography (1:1 petrol ether/ethyl acetate) to yield the title
compound 34 (16.0 g, 95%) as a white solid. Mp 73e75 ꢀC; Rf 0.35
4.1.7. (R)-tert-Butyl
1-hydroxy-3-(4-(undec-10-enyloxy)phenyl)
propan-2-ylcarbamate (15). LiBH4 (5.90 g, 270 mmol) was added
portionwise to a stirring solution of (R)-methyl 2-((tert-butox-
ycarbonyl)amino)-3-(4-(undec-10-en-1-yloxy)phenyl)propanoate
14 (60.4 g, 130 mmol) in THF (1.2 L) at 0 ꢀC. The resulting mixture
was allowed to warm to RT over 16 h. The reaction was quenched
with 1 M aq HCl until effervescing ceased and the aqueous layer
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried (Na2SO4) and concentrated under re-
duced pressure. The resulting residue was triturated with ice-cold
hexane (2ꢃ500 mL) and sonicated briefly. The resulting pre-
cipitate was filtered, washed with hexane and dried in vacuo to
yield the title compound 15 (55 g, 98%) as a white solid. Mp
(1:1 petrol ether/ethyl acetate); ½a D19
ꢁ
þ37.0 (c 1.08, CHCl3); nmax
/
cmꢂ1 3309 (NH), 3258 br (OH), 3074 (Ar CH), 2985 (CH), 2939 (CH),
2862 (CH), 1730 (C]O), 1644 (C]O),1611 (Ar C]C), 1584 (Ar C]C),
1548 (NH), 1511 (Ar C]C), 1477 (Ar C]C), 1265 (CeN), 1246
(CeOeC), 1174 (CeOeC), 1151 (CeO), 1028 (CeOH), 997 (C]C), 917
(C]C), 827 (Ar CH); dH (200 MHz, CDCl3) 7.24e7.09 (3H, m, AreH,
NH), 6.89e6.78 (2H, m, AreH), 5.81 (1H, ddt, J 17.0, 10.4, 6.6, CH]
CH2), 5.10e4.86 (3H, m, CHCH2OH, CH]CH2), 4.15 (2H, q, J 7.1,
67e69 ꢀC; Rf 0.15 (4:1 petrol ether/ethyl acetate); ½a 2D2
ꢁ
þ12.3 (c 2.11,
OCH2CH3), 3.91 (2H, t, J 6.4, OCH2CH2), 3.82e3.69 (2H, m,
CHCl3); nmax/cmꢂ1 3358 br (NH, OH), 2974 (Ar CH), 2920 (CH), 2852
(CH), 1689 (C]O), 1642 (Ar C]C), 1614 (Ar C]C), 1582 (NH), 1528
(Ar C]C), 1510 (Ar C]C), 1268 (NeCOeO), 1241 (CeOeC), 1171
(NeCOeO), 1061 (CeOH), 1035 (CeOH), 1004 (]CH), 906 (]CH);
dH (300 MHz, CDCl3) 7.16e7.08 (2H, m, AreH), 6.89e6.80 (2H, m,
AreH), 5.82 (1H, ddt, J 13.2, 10.3, 6.6, CH]CH2), 5.07e4.90 (2H, m,
]CH2), 4.73 (1H, d, J 7.7, NH), 3.93 (2H, t, J 6.6, OCH2), 3.88e3.72
(1H, m, CHCH2OH), 3.72e3.48 (2H, m, CH2OH), 2.78 (2H, d, J 7.3,
CH2CHCH2), 2.41 (1H, br s, OH), 2.11e1.98 (2H, m, alkyl-H),
1.85e1.71 (2H, m, alkyl-H), 1.52e1.24 (21H, m, alkyl-H, C(CH3)3); dC
(75 MHz, CDCl3) 157.9 (C),156.2 (C), 139.2 (CH),130.1 (CH), 129.4 (C),
114.6 (CH), 114.1 (CH2), 79.7 (C), 68.0 (CH2), 64.4 (CH2), 53.9 (CH),
36.2 (CH2), 33.8 (CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 28.9 (CH2)
(plus two overlapping peaks), 28.3 (CH3), 26.0 (CH2); HRMS (ESI)
[MþH]þ calcd for C25H42NO4 420.3108, found 420.3101.
CHCH2OH), 3.47 (1H, s, OH), 2.20e1.96 (2H, m, alkyl-H), 1.88e1.68
(2H, m, alkyl-H), 1.64e1.48 (2H, m, alkyl-H), 1.45 (3H, s, CH3), 1.42
0
(3H, s, CH3 ), 1.23 (3H, t, J 7.1, OCH2CH3); dC (50 MHz, CDCl3) 174.6
(C), 172.2 (C), 158.4 (C), 138.3 (CH), 130.8 (C), 127.5 (CH), 114.6 (CH2),
114.5 (CH), 67.5 (CH2), 65.9 (CH2), 61.5 (CH2), 55.1 (CH), 49.7 (C),
33.2 (CH2), 28.5 (CH2), 25.1 (CH2), 23.4 (2ꢃCH3 overlapping), 13.8
(CH3); HRMS (ESI) [MþH]þ calcd for C21H32NO5 378.2275, found
378.2275.
4.1.10. (S)-3-(1-(4-(Hex-5-enyloxy)phenyl)-2-hydroxyethylamino)-
2,2-dimethyl-3-oxopropanoic acid (16). A solution of NaOH (10.6 g,
260 mmol) in 1:1 THF/H2O (300 mL) was added to a stirring solu-
tion
of
(S)-ethyl
3-(1-(4-(hex-5-enyloxy)phenyl)-2-
hydroxyethylamino)-2,2-dimethyl-3-oxopropanoate 34 (10.0 g,
26.0 mmol) in 1:1 THF/H2O (500 mL). The resulting mixture was
stirred at 45 ꢀC for 4 h. The reaction was cooled to 0 ꢀC and
quenched with 6 M aq HCl until pH 1 was reached. The mixture was
extracted with ethyl acetate and DCM and the combined organic
layers were washed with water, brine and dried (MgSO4). The
resulting solution was concentrated under reduced pressure to
yield the title compound 16 (8.20 g, 89%) as a white solid. Mp
4.1.8. (R)-2-Amino-3-(4-(undec-10-enyloxy)phenyl)propan-1-ol
(6). p-Toluenesulfonic acid monohydrate (53.9 g, 280 mmol) was
added portionwise to a stirring solution of (R)-tert-butyl 1-hydroxy-
3-(4-(undec-10-en-1-yloxy)phenyl)propan-2-ylcarbamate 15 (59.4 g,
140 mmol) in 1:1 THF/H2O (1.5 L). The resulting mixture was heated
at reflux for 18 h. After cooling, the reaction was quenched with 2 M
aq NaOH (500 mL) and the aqueous layer extracted with ethyl acetate
(250 mL) and then DCM (250 mL). The combined organic layers were
118e121 ꢀC; Rf 0.05 (9:1 ethyl acetate/petrol ether); ½a 2D1
þ73.0 (c
ꢁ
1.26, CHCl3); nmax/cmꢂ1 3308 br (OH/NH), 2980 (Ar CH), 2935 (CH),
2865 (CH), 1715 (Ar CH), 1679 (C]O), 1655 (C]O), 1613 (Ar C]C),

64
P.E. Glen et al. / Tetrahedron 69 (2013) 57e68
1559 (NH), 1512 (Ar C]C), 1466 (Ar C]C), 1389 (CeN), 1247
(CeOeC/CeN), 1175 (CeN), 1156 (CeO), 1028 (CeOH), 992 (]CH),
900 (]CH), 827 (Ar CH), 810 (NH); dH (200 MHz, CDCl3) 7.92 (1H, d,
J 5.8, NH), 7.20 (2H, d, J 8.3, AreH), 6.82 (2H, d, J 8.3, AreH), 5.83 (1H,
ddt, J 16.8, 10.1, 6.6, CH]CH2), 5.22e4.92 (3H, m, CHCH2OH, ]CH2),
4.04e3.70 (4H, m, CH2OH, OCH2), 2.24e2.04 (2H, m, alkyl-H),
1.90e1.67 (2H, m, alkyl-H), 1.65e1.35 (8H, m, alkyl-H); dC (50 MHz,
CDCl3) 177.2 (C), 173.8 (C), 158.6 (C), 138.5 (CH), 130.6 (C), 127.6 (CH),
114.7 (CH2), 114.7 (CH), 67.7 (CH2), 64.8 (CH2), 55.4 (CH), 49.5 (C),
33.4 (CH2), 28.6 (CH2), 25.3 (CH2), 23.5 (CH3), 23.4 (CH3); HRMS
(ESI) [MþH]þ calcd for C19H28NO5 350.1962, found 350.1965.
purified by column chromatography (1:1 ethyl acetate/petrol ether
to 5% methanol/ethyl acetate) to yield the title compound 2 (1.42 g,
65%) as a white solid. Mp 186e190 ꢀC; Rf 0.08 (4:1 ethyl acetate/
petrol ether); ½a D21
ꢁ
þ68.7 (c 0.99, CHCl3); nmax/cmꢂ1 3428 (NH),
3368 br (OH), 2924 (CH), 2854 (CH), 1655 (C]O), 1633 (NH), 1611
(Ar C]C), 1582 (Ar C]C), 1530 (NeC]O), 1513 (Ar C]C), 1470 (Ar
C]C), 1243 (CeN, CeOeC), 1179 (CeOH), 1073 (CeOeC), 1038
(CeOeC, CeOH), 826 (Ar CH); dH (400 MHz, CDCl3) 7.16e7.07 (4H,
m, AreH), 6.94 (1H, d, J 7.0, NH), 6.88e6.81 (4H, m, AreH), 6.56 (1H,
d, J 7.9, NH), 4.92e4.84 (1H, m, CHCH2OH), 4.15e4.03 (1H, m,
0
CH(CH2)2), 4.00e3.90 (4H, m, OCH2, OCH2 ), 3.79 (1H, dd, J 11.2, 4.4,
CHCHHOH), 3.74 (1H, dd, J 11.2, 6.2, CHCHHOH), 3.57 (1H, dd, J 10.9,
3.8, CH2CHCHHOH), 3.51 (1H, dd, J 10.9, 5.0, CH2CHCHHOH), 2.79
(2H, d, J 7.3, CH2CHCH2OH), 1.83e1.871 (4H, m, alkyl-H), 1.60e1.10
(28H, m, alkyl-H); dC (101 MHz, CDCl3) 174.1 (C]O), 173.8 (C]O),
159.0 (AreC), 158.2 (AreC), 130.8 (AreC), 130.3 (AreCH), 129.5
(AreC), 127.7 (AreCH), 115.1 (AreCH), 115.0 (AreCH), 68.2 (OCH2),
66.3 (CHCH2OH), 63.9 (CH2CHCH2OH), 55.7 (CHCH2OH), 53.3
(CH(CH2)2), 50.1 (C(CH3)2), 36.0 (CH2CHCH2OH), 29.1 (alkyl-CH2),
29.1 (alkyl-CH2), 29.0 (alkyl-CH2), 28.9 (alkyl-CH2) (plus six over-
lapping peaks), 28.8 (alkyl-CH2), 28.7 (alkyl-CH2), 25.9 (alkyl-CH2),
4.1.11. N1-((S)-1-(4-(Hex-5-enyloxy)phenyl)-2-hydroxyethyl)-N3-((R)-
1-hydroxy-3-(4-(undec-10-enyloxy)phenyl)propan-2-yl)-2,2-
dimethylmalonamide (3). (R)-2-Amino-3-(4-(undec-10-enyloxy)phe-
nyl)propan-1-ol 6 (4.31 g,13.5 mmol) was added to a stirring solution
of (S)-3-(1-(4-(hex-5-enyloxy)phenyl)-2-hydroxyethylamino)-2,2-
dimethyl-3-oxopropanoic acid 16 (4.20 g, 12.0 mmol), O-(benzo-
triazol-1-yl)-N,N,N0,N0-tetramethyluronium tetrafluoroborate (TBTU)
(4.30 g,13.0 mmol) and N,N-diisopropylethylamine (DIPEA) (2.30 mL,
13.4 mmol) in 4:1 DCM/DMF (400 mL). The resulting mixture was
stirred at RT for 93 h. The reaction was quenched with water
(400 mL) and the aqueous layer extracted with ethyl acetate. The
combined organic layers were dried (MgSO4) and concentrated under
reduced pressure. The resulting residue was purified by column
chromatography (1:1 ethyl acetate/petrol ether to 95:5 ethyl acetate/
methanol) to yield the title compound 3 (5.70 g, 73%) as a white solid.
25.7 (alkyl-CH2), 24.2 (CH3), 23.2 (CH3 ); HRMS (ESI) [MþH]þ calcd
0
for C37H57N2O6 625.4211, found 625.4205.
4.1.13. Macrocycle 17. Thionyl chloride (2.00 mL, 27.0 mmol) was
added to a stirring suspension of macrocycle 2 (1.42 g, 2.27 mmol)
in DCM (50 mL). The resulting mixture was stirred at RT for 23 h,
then concentrated under reduced pressure and the resulting resi-
due purified by column chromatography (49:1 DCM/ethyl acetate)
to yield the title compound 17 (1.43 g, 94%) as a white solid. Mp
Mp 77e78 ꢀC; Rf 0.47 (4:1 ethyl acetate/petrol ether); ½a 2D0
þ37.9 (c
ꢁ
0.95, CHCl3); nmax/cmꢂ1 3335 br (OH/NH), 2926 (CH), 2855 (CH), 1640
(C]O), 1613 (Ar C]C), 1583 (NH), 1510 (Ar C]C), 1471 (Ar C]C),
1243 (CeOeC), 1176 (CeO), 1034 (CeOH), 994 (]CH), 909 (]CH),
829 (Ar CH); dH (400 MHz, CDCl3) 7.22e7.04 (5H, m, AreH, NH),
6.89e6.78 (4H, m, AreH), 6.65 (1H, d, J 7.9, NH), 5.89e5.77 (2H, m,
145e148 ꢀC; Rf 0.25 (49:1 DCM/ethyl acetate); ½a 2D1
þ37.9 (c 0.58,
ꢁ
CHCl3); nmax/cmꢂ1 3376 (NH), 2924 (CH), 2854 (CH), 1652 (C]O),
1612 (Ar C]C), 1584 (NH), 1510 (NeC]O), 1471 (Ar C]C), 1240
(CeOeC), 1179 (Ar CH), 1033 (CeOeC), 836 (Ar CH), 749 (CeCl); dH
(400 MHz, CDCl3) 7.17e7.10 (4H, m, AreH), 7.08 (1H, d, J 7.6, NH),
6.94e6.71 (4H, m, AreH), 6.47 (1H, d, J 8.2, NH), 5.17e5.09 (1H, m,
CHCH2Cl), 4.37e4.22 (1H, m, CH(CH2)2), 4.04e3.87 (4H, m, OCH2,
0
0
CH]CH2, CH]CH2 ), 5.08e4.90 (5H, m, CHCH2OH, ]CH2, ]CH20),
4.16e4.05 (1H, m, CH(CH2)2), 3.96e3.88 (4H, m, OCH2, OCH2 ),
3.85e3.72 (2H, m, CH2OH), 3.63 (1H, dd, J 11.2, 3.8, CH2CHCHHOH),
3.55 (1H, dd, J 11.2, 5.6, CH2CHCHHOH), 2.94 (2H, br s, OH), 2.82 (1H,
dd, J 13.8, 6.7, CHHCHCH2OH), 2.73 (1H, dd, J 13.8, 7.6, CHHCHCH2OH),
2.18e2.00 (4H, m, alkyl-H), 1.84e1.72 (4H, m, alkyl-H), 1.61e1.51 (2H,
0
OCH2 ), 3.75 (2H, d, J 5.6, CHCH2Cl), 3.44 (1H, dd, J 11.4, 3.5,
CH2CHCHHCl), 3.38 (1H, dd, J 11.4, 4.4, CH2CHCHHCl), 2.87 (1H, dd, J
13.5, 5.9, CHHCHCH2Cl), 2.79 (1H, dd, J 13.5, 8.8, CHHCHCH2Cl),
1.87e1.66 (4H, m, alkyl-H), 1.57e1.25 (28H, m, alkyl-H); dC
(101 MHz, CDCl3) 173.3 (C]O), 172.3 (C]O), 158.9 (AreC), 158.2
(AreC), 130.2 (AreC), 130.1 (AreCH), 128.4 (AreC), 127.6 (AreCH),
0
m, alkyl-H), 1.49e1.28 (18H, m, CH3, CH3 , alkyl-H); dC (101 MHz,
CDCl3) 174.1 (C]O), 173.8 (C]O), 158.7 (AreC), 157.9 (AreC), 139.2
0
(CH]CH2), 138.5 (CH]CH2 ), 130.5 (AreC, AreCH), 130.1 (AreCH),
129.2 (AreC), 127.6 (AreCH), 114.8 (]CH2), 0114.7 (AreCH), 114.6
(CH2), 114.1 (AreCH), 68.0 (OCH2), 67.8 (OCH2 ), 66.2 (CH2OH), 64.0
(CH2CHCH2OH), 55.4 (CHCH2OH), 53.3 (CH(CH2)2), 49.8 (C(CH3)2),
35.9 (CH2CHCH2OH), 33.8 (alkyl-CH2), 33.4 (alkyl-CH2), 29.5 (alkyl-
CH2), 29.4 (alkyl-CH2), 29.3 (alkyl-CH2), 29.1 (alkyl-CH2), 28.9 (alkyl-
CH2) (plus one overlapping peak), 28.7 (alkyl-CH2), 26.0 (alkyl-CH2),
0
114.9 (AreCH), 114.8 (AreCH), 67.9 (OCH2), 67.8 (OCH2 ), 53.6
(CHCH2Cl), 51.5 (CH(CH2)2), 49.8 (C(CH3)2), 47.2 (CHCH2Cl), 45.9
(CH2CHCH2Cl), 36.2 (CH2CHCH2Cl), 29.2 (alkyl-CH2), 29.1 (alkyl-
CH2), 29.1 (alkyl-CH2), 28.9 (alkyl-CH2), 28.8 (alkyl-CH2) (plus six
overlapping peaks), 25.8 (alkyl-CH2), 25.7 (alkyl-CH2), 24.6 (CH3),
22.3 (CH3); HRMS (ESI) [MþH]þ calcd for C37H5535Cl2N2O4
661.3533, found 661.3533.
þ
0
25.3 (alkyl-CH2), 23.8 (CH3), 23.6 (CH3 ); HRMS (ESI) [MþH] calcd
for C39H59N2O6 651.4368, found 651.4362.
4.1.12. Macrocycle 2. A solution of N1-((S)-1-(4-(hex-5-enyloxy)
phenyl)-2-hydroxyethyl)-N3-((R)-1-hydroxy-3-(4-(undec-10-
enyloxy) phenyl)propan-2-yl)-2,2-dimethylmalonamide 3 (2.30 g,
3.53 mmol) in DCM (130 mL) was added dropwise to a stirring
solution of Grubbs first generation catalyst (0.29 g, 0.35 mmol) in
DCM (930 mL) under an argon atmosphere. The resulting mixture
was heated at reflux for 7 days. The reaction was cooled to RT and
concentrated under reduced pressure. The resulting residue was
passed through a silica column (9:1 petrol ether/ethyl acetate to 5%
methanol/ethyl acetate) to remove unreacted 3. The resulting crude
product was dissolved in THF (200 mL) and 10% w/w Pd/C (0.87 g)
added. The resulting mixture was placed under a hydrogen atmo-
sphere and stirred at RT for 6 h. The mixture was then flushed
through a plug of Celite with THF and the resulting solution con-
centrated under reduced pressure. The resulting residue was
4.1.14. Macrocycle 1. Tetrabutylammonium fluoride (TBAF) (1.0 M
in THF, 7.60 mL, 7.60 mmol) was added to a stirring solution of
macrocycle 17 (1.25 g, 1.89 mmol) in DCM (100 mL). The resulting
mixture was stirred at RT for 43 h. The mixture was concentrated
under reduced pressure and the resulting residue dissolved in DCM
(100 mL). The solution was washed with satd aq sodium citrate
(3ꢃ100 mL), brine, dried (MgSO4) and concentrated under reduced
pressure. The resulting residue was purified by alumina column
chromatography (7:1 hexane/ethyl acetate, 0.4% Et3N) to yield the
title compound 1 (0.57 g, 51%) as a white gum. Mp 62e65 ꢀC; Rf 0.18
(1:1 ethyl acetate/petrol ether); ½a D21
ꢁ
ꢂ45.4 (c 0.44, CHCl3); nmax
/
cmꢂ1 2926 (CH), 2855 (CH), 1656 (C]N), 1612 (Ar C]C), 1583 (Ar
C]C), 1512 (Ar C]C), 1472 (Ar C]C), 1247 (CeOeC), 1116 (CeOeC),
831 (Ar CH); dH (400 MHz, CDCl3) 7.19e7.08 (4H, m, AreH),
6.87e6.82 (4H, m, AreH), 5.12 (1H, dd, J 10.0, 6.5, H-5), 4.55 (1H, dd,

P.E. Glen et al. / Tetrahedron 69 (2013) 57e68
65
J 10.0, 8.5, H-4a), 4.51e4.43 (1H, m, H-30), 4.23 (1H, dd, J 9.4, 8.5, H-
31a), 4.14 (1H, dd, J 8.5, 6.5,0H-4b), 4.04 (1H, dd, J 8.5, 7.2, H-31b),
3.97 (4H, t, J 6.5, OCH2, OCH2 ), 3.09 (1H, dd, J 13.8, 5.0, H-29a), 2.69
(1H, dd, J 13.8, 8.2, H-29b), 1.83e1.73 (4H, m, alkyl-H), 1.60 (3H, s,
4.4, CH2CHCHHCl), 3.51 (1H, dd, J 11.4, 3.7, CH2CHCHHCl), 2.95 (2H,
d, J 7.7, CH2CHCH2Cl),1.50 (3H, s, CH3),1.45 (3H, s, CH3’); dC (75 MHz,
CDCl3) 173.3 (C), 172.8 (C), 138.3 (C), 136.7 (C), 129.2 (CH), 128.9
(CH), 128.8 (CH), 128.2 (CH), 127.0 (CH), 126.5 (CH), 54.1 (CH2), 51.1
(CH2), 49.5 (C), 47.5 (CH), 46.3 (CH), 37.4 (CH2), 24.0 (CH3), 23.7
(CH3); HRMS (ESI) [MþH]þ calcd for C22H2735Cl2N2O2 421.1444,
found 421.1442.
0
CH3), 1.59 (3H, s, CH3 ), 1.54e1.26 (22H, m, alkyl-H); dC (101 MHz,
CDCl3) 169.8 (N]CO), 169.6 (N]CO0), 158.5 (AreC), 157.8 (AreC),
134.8 (AreC), 130.5 (AreCH), 129.2 (AreC), 127.8 (AreCH), 114.8
(AreCH), 114.6 (AreCH), 75.7 (C-4), 71.7 (C-31), 68.9 (C-5), 68.0
0
(OCH2), 67.8 (OCH2 ), 67.1 (C-30), 40.1 (C-29), 38.6 (C(CH3)2), 29.3
4.1.17. (R)-4-Benzyl-2-(2-((S)-4-phenyl-4,5-dihydrooxazol-2-yl)
propan-2-yl)-4,5-dihydrooxazole (20). TBAF (1.0 M in THF, 5.50 mL,
5.50 mmol) was added to a stirring solution of N1-((S)-2-chloro-1-
phenylethyl)-N3-((R)-1-chloro-3-phenylpropan-2-yl)-2,2-dimethyl-
malonamide 36 (56.3 mg, 1.34 mmol) in THF (50 mL). The resulting
mixture was stirred at RT for 18 h, concentrated under reduced pres-
sure and the resulting residue dissolved in DCM (100 mL). The solution
was washed with satd aq sodium citrate (3ꢃ100 mL), brine, dried
(MgSO4) and concentrated under reduced pressure. The resulting
residuewas purified by alumina column chromatography (7:3 hexane/
ethyl acetate, 0.4% Et3N) to yield the title compound 20 (36.2 mg, 80%)
(alkyl-CH2), 29.3 (alkyl-CH2), 29.2 (alkyl-CH2), 29.1 (alkyl-CH2), 29.1
(alkyl-CH2), 29.0 (alkyl-CH2), 29.0 (alkyl-CH2), 29.0 (alkyl-CH2)
(plus four overlapping peþaks), 25.9 (alkyl-CH2), 24.6 (CH3), 23.6
0
(CH3 ); HRMS (ESI) [MþH] calcd for C37H53N2O4 589.4000, found
589.3987.
The following three-step procedure forms C1-Box ligand 20 via
35 and 36.
4.1.15. N1-((S)-2-Hydroxy-1-phenylethyl)-N3-((R)-1-hydroxy-3-
phenylpropan-2-yl)-2,2-dimethylmalonamide (35). A solution of N-
(3-dimethylaminopropyl)-N0-ethylcarbo diimide hydrochloride
(EDCI) (84.1 mg, 4.39 mmol) in CHCl3 (5 mL) was added dropwise to
a stirring solution of (S)-3-(2-hydroxy-1-phenylethylamino)-2,2-
dimethyl-3-oxopropanoic acid 33 (99.9 mg, 3.97 mmol), 1-
hydroxybenzotriazole hydrate (HOBt) (62.6 mg, 4.63 mmol) and
Et3N (1.40 mL, 10.0 mmol) in CHCl3 (37 mL) at 0 ꢀC. The resulting
mixture was stirred at 0 ꢀC for 1 h. A solution of (R)-2-amino-3-
phenylpropan-1-ol (66.2 mg, 4.38 mmol) in CHCl3 (7 mL) was
added dropwise. The resulting solution was warmed to RT and
stirred for 41 h. The reaction was quenched with 3 M aq HCl (12 mL)
and the aqueous layer extracted with CHCl3. The combined organic
layers were washed with brine, dried (MgSO4) and concentrated
under reduced pressure. The resulting residue was purified by
column chromatography (9:1 ethyl acetate/petrol ether) to yield
the title compound 35 (1.05 g, 69%) as a pale yellow solid. Mp
as a colourless oil. Rf 0.10 (3:7 hexane/ethyl acetate); ½a D20
ꢂ51.9 (c 1.31,
ꢁ
CHCl3); nmax/cmꢂ1 3059 (Ar CH), 3028 (Ar CH), 2984 (CH), 2936 (CH),
2901 (CH), 1651 (N]C),1604 (Ar C]C),1495 (Ar C]C),1455 (Ar C]C),
1145 (CeO), 1116 (CeO), 979 (CeN), 921 (Ar CH), 756 (Ar CH), 700 (Ar
CH); dH (300 MHz, CDCl3) 7.40e7.20 (10H, m, AreH), 5.22 (1H, dd, J 9.9,
7.7, OCH2CHN), 4.65 (1H, dd, J 10.1, 8.3, OCHHCHN0), 4.54e4.41 (1H, m,
OCH2CHN0), 4.26 (1H, dd, J 9.9, 8.8, OCHHCHN), 4.18e4.03 (2H, m,
OCHHCHN, OCHHCHN0), 3.16 (1H, dd, J 13.8, 5.0, ArCHHCH), 2.72 (1H,
0
dd, J 13.8, 8.6, ArCHHCH), 1.63 (3H, s, CH3), 1.59 (3H, s, CH3 ); dC
(75 MHz, CDCl3) 170.3 (C), 169.4 (C), 142.5 (C), 137.7 (C), 129.5 (CH),
128.7 (CH), 128.5 (CH), 127.6 (CH), 126.7 (CH), 126.5 (CH), 75.5 (CH2),
72.1 (CH2), 69.5 (CH), 67.1 (CH), 41.4 (CH2), 38.7 (C), 24.4 (2ꢃCH3
overlapping); HRMS (ESI) [MþH]þ calcd for C22H25N2O2 349.1911,
found 349.1908.
119e122 ꢀC; Rf 0.30 (9:1 ethyl acetate/petrol ether); ½a 2D0
ꢁ
þ54.9 (c
4.1.18. Prop-2-ynyl 3,3,3-tris(4-chlorophenyl)propanoate (29). EDCI
(1.98 g, 10.3 mmol) was added to a solution of propargyl alcohol
(0.600 mL, 10.3 mmol) and 3,3,3-tris(4-chlorophenyl)propionic
acid (4.03 g, 9.93 mmol) in DCM (100 mL). 4-(Dimethylamino)
pyridine (DMAP) (13.3 mg, 1.09 mmol) was added and the resulting
mixture was stirred at RT for 5 h. The reaction was quenched with
water (100 mL) and the aqueous layer extracted with DCM. The
combined organic layers were washed with brine, dried (MgSO4)
and concentrated under reduced pressure. The resulting residue
was purified by column chromatography (4:1 hexane/ethyl acetate)
to yield the title compound 29 (3.83 g, 83%) as a white solid. Mp
88e89 ꢀC; Rf 0.55 (4:1 hexane/ethyl acetate); nmax/cmꢂ1 3290
(^CH), 3282 (^CH), 3075 (Ar CH), 2948 (CH), 2129 (C^C), 1729
(C]O), 1589 (Ar C]C), 1490 (Ar C]C), 1441 (Ar C]C), 1269 (^CH),
1219 (Ar CH), 1137 (CeO), 1093 (Ar CeCl), 803 (Ar CH), 688 (^CH);
dH (400 MHz, C2D6O) 7.28e7.08 (6H, m, AreH), 7.12e6.94 (6H, m,
AreH), 4.36 (2H, d, J 2.5, CH2C^CH), 3.61 (2H, s, CH2COO), 2.33 (1H,
t, J 2.5, ^CH); dC (101 MHz, C3D6O2) 169.4 (C), 143.9 (C), 132.7 (C),
130.3 (CH), 128.3 (CH), 77.2 (CH), 74.9 (C), 54.6 (C), 52.0 (CH2), 45.8
(CH2); HRMS (ESI) [MþNa]þ calcd for C24H1735Cl3NaO2 465.0186,
found 465.0183.
1.02, CHCl3); nmax/cmꢂ1 3315 (OH/NH), 3275 (OH/NH), 3062 (Ar
CH), 2942 (CH), 1633 (C]O), 1523 (NeC]O), 1495 (Ar C]C), 1453
(Ar C]C), 1285 (CeN), 1056 (CeOH), 1032 (CeOH), 911 (Ar CH), 735
(Ar CH), 698 (Ar CH); dH (300 MHz, CDCl3) 7.38e7.15 (11H, m, AreH,
NH), 6.67 (1H, d, J 8.1, NH), 5.07e4.93 (1H, m, CHCH2OH), 4.23e4.06
(1H, m, CHCH2OH0), 3.85 (1H, dd, J 11.4, 4.0, CHCHHOH), 3.77 (1H,
dd, J 11.7, 6.6, CHCHHOH0), 3.63 (1H, dd, J 11.7, 4.0, CHCHHOH0), 3.54
(1H, dd, J 11.4, 5.1, CHCHHOH), 2.89 (1H, dd, J 13.6, 6.6, CHHCHCH2),
2.80 (2H, dd, J 13.6, 7.7, CHHCHCH2), 1.41 (3H, s, CH3), 1.35 (3H, s,
0
CH3 ); dC (75 MHz, CDCl3) 174.0 (C), 173.8 (C), 138.8 (C), 137.5 (C),
129.2 (CH), 128.8 (CH), 128.5 (CH), 127.8 (CH),126.6 (CH),126.5 (CH),
66.0 (CH2), 63.9 (CH2), 55.8 (CH), 53.2 (CH), 49.8 (C), 36.7 (CH2), 23.6
(CH3), 23.5 (CH3); HRMS (ESI) [MþH]þ calcd for C22H29N2O4
385.2122, found 385.2122.
4.1.16. N1-((S)-2-Chloro-1-phenylethyl)-N3-((R)-1-chloro-3-phenyl
propan-2-yl)-2,2-dimethylmalonamide
(36). Thionyl
chloride
(1.60 mL, 21.9 mmol) was added to a stirring suspension of N1-((S)-
2-hydroxy-1-phenylethyl)-N3-((R)-1-hydroxy-3-phenylpropan-2-
yl)-2,2-dimethylmalonamide 35 (74.0 mg, 1.92 mmol) in DCM
(40 mL). The resulting mixture was stirred at RT for 19 h, then
concentrated under reduced pressure and the resulting residue
purified by column chromatography (49:1 DCM/ethyl acetate) to
yield the title compound 36 (0.681 g, 85%) as a white solid. Mp
4.1.19. 3-Bromoprop-2-ynyl
3,3,3-tris(4-chlorophenyl)propanoate
(22). Silver nitrate (28.8 g, 1.69 mmol) was added to a stirring
suspension of prop-2-ynyl 3,3,3-tris(4-chlorophenyl)propanoate
29 (2.00 g, 4.51 mmol) and NBS (90.0 mg, 5.06 mmol) in acetone
(50 mL). The flask was protected from light and the mixture stirred
at RT for 1 h. The reaction was diluted with petrol ether (50 mL) and
washed with water. The aqueous layer was extracted with 1:1
petrol ether/diethyl ether. The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure to yield the title
compound 22 (2.5 g, 100%) as a white solid. Mp 116e188 ꢀC; Rf 0.75
157e160 ꢀC; Rf 0.64 (49:1 DCM/ethyl acetate); ½a 2D1
þ42.3 (c 1.04,
ꢁ
CHCl3); nmax/cmꢂ1 3310 (NH), 3063 (Ar CH), 3028 (Ar CH), 2972
(CH), 1637 (C]O), 1554 (NeC]O), 1526 (NeC]O), 1496 (Ar C]C),
1455 (Ar C]C), 699 (CeCl); dH (300 MHz, CDCl3) 7.43e7.22 (11H, m,
AreH, NH), 6.68 (1H, d, J 8.1, NH), 5.33e5.25 (1H, m, CHCH2Cl), 4.46
(1H, tdd, J 7.7, 4.4, 3.7, CH2CHCH2Cl), 3.85 (1H, dd, J 11.4, 5.1,
CHCHHCl), 3.78 (1H, dd, J 11.4, 6.2, CHCHHCl), 3.60 (1H, dd, J 11.4,

66
P.E. Glen et al. / Tetrahedron 69 (2013) 57e68
(9:1 petrol ether/ethyl acetate); nmax/cmꢂ1 3083 (Ar CH), 2934 (CH),
2873 (CH), 2229 (C^C),1748 (C]O),1591 (Ar C]C),1490 (Ar C]C),
1326 (CeO), 1195 (Ar CH), 1183 (Ar CH), 1137 (CeO), 1092 (Ar CeCl),
1012 (CeBr), 817 (Ar CH); dH (300 MHz, CDCl3) 7.34e7.23 (6H, m,
AreH), 7.19e7.05 (6H, m, AreH), 4.48 (2H, s, CH2C^CBr), 3.70 (2H,
s, CH2COO); dC (75 MHz, CDCl3) 169.4 (C), 143.9 (C), 132.8 (C), 130.3
(CH), 128.3 (CH), 73.5 (C), 54.6 (C), 52.8 (CH2), 47.3 (C), 45.7 (CH2);
HRMS (ESI) [MþH]þ calcd for C24H1779Br35Cl3O2 520.9472, found
520.9479.
bromoprop-2-ynyl
3,3,3-tris(4-chlorophenyl)propanoate
22
(1 equiv) in THF (0.05 M) was added. The resulting mixture was
warmed to RT and stirred until the reaction was complete. The
reaction was quenched with 17.5% aq ammonia solution satd with
ethylenediaminetetraacetic acid (EDTA) and stirred under air for
40 min. The aqueous layer was extracted with DCM and the com-
bined organic layers washed with brine, dried (MgSO4) and con-
centrated under reduced pressure. The mixture was analyzed by 1H
NMR spectroscopic analysis (Table 1). For characterization, a sam-
ple was purified by column chromatography (hexane to 9:1 hex-
ane/ethyl acetate) to yield thread 23 as a white solid. Mp 90e94 ꢀC;
Rf 0.38 (9:1 hexane/ethyl acetate); nmax/cmꢂ1 2962 (Ar CH), 2903
(CH), 2868 (CH), 2258 (C^C), 1749 (C]O), 1606 (Ar C]C), 1505 (Ar
C]C), 1492 (Ar C]C), 1248 (CeOeC), 1141 (CeO), 1096 (Ar CeCl),
1054 (CeOeC), 824 (Ar CH); dH (400 MHz, CDCl3) 7.28e7.23 (10H,
m, AreH), 7.17e7.07 (16H, m, AreH), 6.82e6.75 (2H, m, AreH), 4.51
(2H, s, OCH2C^C), 4.05 (2H, t, J 6.6, OCH2CH2), 3.68 (2H, s, CH2COO),
2.56 (2H, t, J 6.6, CH2C^C), 2.04 (2H, quin., J 6.6, CH2CH2CH2), 1.32
(27H, s, CH3); dC (101 MHz, CDCl3) 169.4 (C), 156.5 (C), 148.3 (C),
144.1 (C), 143.9 (C), 139.8 (C), 132.8 (C), 132.3 (CH), 130.7 (CH), 130.3
(CH), 128.3 (CH), 124.0 (CH), 113.0 (CH), 81.2 (C), 71.7 (C), 68.8 (C),
65.8 (CH2), 64.7 (C), 63.1 (C), 54.6 (C), 52.6 (CH2), 45.8 (CH2), 34.3
(C), 31.6 (CH3), 22.7 (CH2), 14.1 (CH2); HRMS (ESI) [MþNH4]þ calcd
for C66H6935Cl3NO3 1028.4338, found 1028.4340.
Thread 24 was also isolated from the reaction as a white solid.
Mp 84e88 ꢀC; Rf 0.14 (9:1 petrol ether/ethyl acetate); nmax/cmꢂ1
3075 (Ar CH), 3040 (Ar CH), 2932 (CH), 2254 (C^C), 1747 (C]O),
1590 (Ar C]C), 1574 (Ar C]C), 1490 (Ar C]C), 1369 (CH), 1193 (Ar
CH), 1138 (CeO), 1094 (Ar CeCl), 808 (Ar CH); dH (300 MHz, CDCl3)
7.34e7.22 (12H, m, AreH), 7.20e7.09 (12H, m, AreH), 4.54 (4H, s,
CH2C^C), 3.71 (4H, s, CH2COO); dC (75 MHz, CDCl3) 169.3 (C), 143.9
(C), 132.8 (C), 130.3 (CH), 128.4 (CH), 73.2 (C), 70.3 (C), 54.6 (C), 52.3
(CH2), 45.7 (CH2); HRMS (ESI) [MþNH4]þ calcd for C48H3635Cl6NO4
900.0770, found 900.0773.
4.1.20. 3-Hydroxypropyl
3,3,3-tris(4-chlorophenyl)propanoate
(37). 3,3,3-Tris(4-chlorophenyl)propanoic acid (4.08 g, 12.3 mmol),
DMAP (14.3 mg, 1.17 mmol) and EDCI (2.35 g, 12.3 mmol) were
added sequentially to
a stirring solution of propane-1,3-diol
(0.810 mL, 11.2 mmol) in DCM (180 mL). The resulting mixture
was stirred at RT for 22 h. The reaction was quenched with water
(100 mL) and the aqueous layer extracted with DCM. The combined
organic layers were dried (MgSO4) and concentrated under reduced
pressure. The resulting residue was purified by column chroma-
tography (9:1 petrol ether/ethyl acetate to 1:1 petrol ether/ethyl
acetate) to yield the title compound 37 (3.48 g, 67%) as a white solid.
Mp 89e90 ꢀC; Rf 0.05 (4:1 petrol ether/ethyl acetate); nmax/cmꢂ1
3401 br (OH), 3067 (Ar CH), 3032 (Ar CH), 2961 (CH), 2888 (CH),
1731 (C]O), 1590 (Ar C]C), 1574 (Ar C]C), 1491 (Ar C]C), 1150
(CeOeC), 1096 (Ar CeCl), 1053 (CeOH), 1013 (CeOeC), 811 (Ar CH),
733 (CeCl); dH (300 MHz, CDCl3) 7.21e7.15 (6H, m, AreH), 7.12e7.00
(6H, m, AreH), 3.90 (2H, t, J 6.1, OCH2), 3.56 (2H, s, CH2COO), 3.35
(2H, t, J 6.1, CH2OH), 1.54 (3H, quin., J 6.1, CH2CH2CH2); dC (75 MHz,
CDCl3) 170.6 (C), 144.1 (C), 132.7 (C), 130.3 (CH), 128.3 (CH), 61.6
(CH2), 59.0 (CH2), 54.7 (C), 46.1 (CH2), 31.4 (CH2); HRMS (ESI)
[MþNH4]þ calcd for C24H2535Cl3NO3 480.0895, found 480.0885.
4.1.21. 3-(3,3,3-Tris(4-Chlorophenyl)propanoyloxy)propyl
acrylate
(25). Et3N (3.80 mL, 27.3 mmol) was added to a stirring solution of
3-hydroxypropyl 3,3,3-tris(4-chlorophenyl)propanoate 37 (2.73 g,
5.89 mmol) in DCM (75 mL) under an argon atmosphere. The
resulting mixture was cooled to 0 ꢀC and DMAP (70.0 mg,
0.590 mmol) and acrylolyl chloride (1.10 mL, 14.0 mmol) were
added. The resulting mixture was stirred for 2 h. The reaction was
quenched with water (75 mL) and the aqueous layer extracted with
DCM. The combined organic layers were washed with brine, dried
(MgSO4) and concentrated under reduced pressure. The resulting
residue was purified by column chromatography (9:1 petrol ether/
ethyl acetate) to yield the title compound 25 (1.77 g, 63%) as a col-
ourless oil. Rf 0.43 (9:1 petrol ether/ethyl acetate); nmax/cmꢂ1 3070
(Ar CH), 3036 (]CH), 2966 (CH), 2901 (CH), 1721 (C]O), 1636 (C]
C), 1619 (Ar C]C), 1590 (Ar C]C), 1490 (Ar C]C), 1185 (CeOeC),
1147 (CeOeC), 1094 (Ar CeCl), 985 (]CH), 907 (]CH), 811 (]CH),
730 (Ar CH); dH (300 MHz, CDCl3) 7.23e7.12 (6H, m, AreH),
7.11e6.98 (6H, m, AreH), 6.31 (1H, dd, J 17.6, 1.5, ]CHH), 6.01 (1H,
dd, J 17.6, 10.3, CH]CH2), 5.74 (1H, dd, J 10.3, 1.5, CHH), 3.95 (2H, t, J
6.3, CH2OCO), 3.83 (2H, t, J 6.3, CH2OCO0), 3.56 (2H, s, CH2COO), 1.67
(2H, quin., J 6.3, CH2CH2CH2); dC (75 MHz, CDCl3) 170.1 (C),165.9 (C),
144.1 (C), 132.6 (C), 130.9 (CH2), 130.3 (CH), 128.2 (CH), 128.1 (CH),
61.1 (CH2), 60.7 (CH2), 54.6 (C), 46.0 (CH2), 27.6 (CH2); HRMS (ESI):
[MþNH4]þ calcd for C27H2735Cl3NO4 534.1000, found 534.1002.
4.3. General procedure for the oxidative Heck reaction
A solution of palladium(II) acetate (20 mol %) and Box ligand
(1 equiv) in DMF (0.05 M) was stirred at RT for 2.5 h. A solution of 3-
(3,3,3-tris(4-chlorophenyl)propanoyloxy)propyl
acrylate
25
(1 equiv), 4-(3-(4-(tris(4-tert-butyl-phenyl)methyl)phenoxy) pro-
poxy)phenylboronic acid 26 (3 equiv) and benzoquinone (1 equiv)
in CHCl3 (0.05 M) was added. The resulting mixture was placed
under an oxygen atmosphere and heated to 25 ꢀC for 48 h. The
reaction was diluted with DCM, washed with water, dried (MgSO4)
and concentrated under reduced pressure. The mixture was ana-
lyzed by 1H NMR analysis (Table 2). For characterization, a sample
was purified by column chromatography (19:1 petrol ether/ethyl
acetate to 9:1 petrol ether/ethyl acetate) to yield thread 27 as
a white solid. Mp 164e166 ꢀC; Rf 0.16 (9:1 petrol ether/ethyl ace-
tate); nmax/cmꢂ1 2961 (Ar CH), 2905 (CH), 2868 (CH), 1738 (C]O),
1713 (C]O), 1634 (C]C), 1604 (Ar C]C), 1506 (Ar C]C), 1492 (Ar
C]C), 1473 (Ar C]C), 1246 (CeOeC), 1165 (CeO), 1096 (Ar CeCl),
1055 (CeOeC), 826 (Ar CH); dH (400 MHz, CDCl3) 7.66 (1H, d, J 15.6,
CH]CH), 7.47 (2H, s, AreH), 7.31e7.23 (13H, m, AreH), 7.17e7.09
(13H, m, AreH), 6.97e6.91 (2H, m, AreH), 6.84e6.78 (2H, m, AreH),
6.31 (1H, d, J 15.6, OCOCH]CH), 4.23 (2H, t, J 6.2, CH2O), 4.20e4.09
(4H, m, CH2OCO, CH2O0), 3.99 (2H, t, J 6.2, CH2OCO0), 3.67 (2H, s,
CH2COO), 2.30 (2H, quin., J 6.2, CH2CH2CH2), 1.82 (2H, quin., J 6.2,
4.2. General procedure for the CadioteChodkiewicz reaction
0
n-Butyl lithium (1 equiv) was added dropwise to a stirring so-
lution of 4,40,400-((4-(pent-4-ynyloxy)phenyl)methanetriyl) tris(-
tert-butylbenzene) 21 (1 equiv) in THF (0.09 M) at ꢂ78 ꢀC. The
resulting mixture was warmed to 0 ꢀC and stirred for 40 min.
Copper iodide/chloride (1.3 equiv) was added and the resulting
mixture warmed to RT and stirred for 1 h. The reaction mixture was
cooled to ꢂ78 ꢀC and a solution of Box ligand (1 equiv) and 3-
CH2CH2CH2 ), 1.33 (27H, s, CH3); dC (101 MHz, CDCl3) 170.2 (C), 167.1
(C), 160.8 (C), 156.6 (C), 148.3 (C), 144.8 (C), 144.2 (CH), 139.8 (C),
132.7 (C), 132.3 (CH), 130.7 (CH), 130.3 (CH), 129.8 (CH), 128.3 (CH),
127.0 (C), 124.1 (CH), 115.2 (CH), 114.9 (CH), 113.0 (CH), 64.7 (CH2),
64.0 (CH2), 63.1 (C), 61.4 (CH2), 60.7 (CH2), 54.6 (C), 46.1 (CH2), 34.3
(C), 31.4 (CH3), 29.3 (CH2), 27.8 (CH2); HRMS (ESI) [MþNH4]þ calcd
for C73H7935Cl3NO6 1170.4967, found 1170.4984.

P.E. Glen et al. / Tetrahedron 69 (2013) 57e68
67
7. Mobian, P.; Banerji, N.; Bernardinelli, G.; Lacour, J. Org. Biomol. Chem. 2006, 4,
224e231.
4.4. General procedure for the CuAAC click reaction
solution of tetrakis(acetonitrile)copper(I)
8. For reviews of active metal template synthesis of molecular architectures see:
(a) Crowley, J. D.; Goldup, S. M.; Lee, A. L.; Leigh, D. A.; McBurney, R. T. Chem.
Soc. Rev. 2009, 38, 1530e1541; (b) Beves, J. E.; Blight, B. A.; Campbell, C. J.; Leigh,
D. A.; McBurney, R. T. Angew. Chem., Int. Ed. 2011, 50, 9260e9327.
9. For recent reviews on bis-oxazoline ligands, see: (a) Desimoni, G.; Faita, G.;
Jørgensen, K. A. Chem. Rev. 2006, 106, 3561e3651; (b) Rasappan, R.; Laventine,
D.; Reiser, O. Coord. Chem. Rev. 2008, 252, 702e714; (c) Hargaden, G. C.; Guiry,
P. J. Chem. Rev. 2009, 109, 2505e2550.
A
hexa-
fluorophosphate (1 equiv) and Box ligand (1 equiv) in DCM (1 mL)
was stirred for 2.5 h. A solution of prop-2-ynyl 3,3,3-tris(4-chlor-
ophenyl)propanoate 29 (1 equiv) and 4,40,400-((4-(3-azido-propoxy)
phenyl) methanetriyl)tris(tert-butylbenzene) 30 (1 equiv) in DCM
(1.5 mL) was added. The resulting mixture was concentrated under
reduced pressure to the required concentration and the reaction
mixture heated to 25 ꢀC until the reaction was complete. The
resulting mixture was diluted with DCM, washed with 17.5% aq NH3
satd with EDTA, dried (MgSO4) and concentrated under reduced
pressure. The mixture was analyzed by 1H NMR analysis (Table 3).
For characterization, a sample was purified by column chroma-
tography (4:1 petrol ether/ethyl acetate to ethyl acetate) to yield
thread 31 as a white solid. Mp 129e131 ꢀC; Rf 0.14 (4:1 petrol ether/
ethyl acetate); nmax/cmꢂ1 2961 (Ar CH), 2903 (CH), 2868 (CH), 1739
(C]O), 1505 (Ar C]C), 1492 (Ar C]C), 1401 (N]N), 1363 (N]N),
1245 (CeOeC), 1185 (CeOeC), 1146 (CeOeC), 1110 (CeN), 1096 (Ar
CeCl), 1055 (CeOeC), 822 (Ar CH); dH (300 MHz, CDCl3) 7.28e7.19
(14H, m, AreH), 7.15e7.06 (15H, m, AreH, C]CHN), 6.81e6.72 (2H,
m, AreH), 5.00 (2H, s, OCH2C]C), 4.58 (2H, t, J 6.3, NCH2), 3.96 (2H,
t, J 6.3, OCH2CH2), 3.68 (2H, s, CH2COO), 2.38 (2H, quin., J 6.3,
CH2CH2CH2), 1.33 (27H, s, CH3); dC (75 MHz, CDCl3) 170.2 (C), 156.2
(C), 148.4 (C), 144.1 (C), 144.0 (C), 142.1 (C), 140.2 (C), 132.6 (CH),
132.4 (C), 130.7 (CH), 130.3 (CH), 128.2 (CH), 124.1 (CH), 112.9 (CH),
63.8 (C), 63.1 (CH2), 57.8 (CH2), 54.5 (C), 47.3 (CH2), 46.0 (CH2), 34.3
(C), 31.4 (CH3), 30.0 (CH2); HRMS (ESI) [MþH]þ calcd for
C64H6735Cl3N3O3 1030.4243, found 1030.4244.
ꢀ
ꢀ
ꢀ
ꢁ
ꢁ
10. Portada, T.; Roje, M.; Raza, Z.; Caplar, V.; Zinic, M.; Sunjic, V. Eur. J. Org. Chem.
2007, 838e856.
11. As far as we are aware, there are only a few examples of C1-symmetric Box
ligands with different pendant groups (non-macrocyclic), see: (a) Sibi, M. P.;
Venkatraman, L.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 2001, 123, 8444e8445;
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ꢁ
Reiser, O.; Roldan, M.; Villalba, I. Chem.dEur. J. 2007, 13, 8830e8839; (d) Or-
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Gissibl, A.; Reiser, O. J. Org. Chem. 2003, 68, 10166e10168; (b) Lang, K.; Park, J.;
Hong, S. J. Org. Chem. 2010, 75, 6424e6435.
13. For C1-symmetric Pybox (non-macrocyclic), see: (a) Nishiyama, H.; Soeda, N.;
Naito, T.; Motoyama, Y. Tetrahedron: Asymmetry 1998, 9, 2865e2869; (b) Sada,
K.; Tateishi, Y.; Shinkai, S. Chem. Lett. 2004, 33, 582e583; (c) Cornejo, A.; Fraile,
J. M.; García, J. I.; Gil, M. J.; Martínez-Merino, V.; Mayoral, J. A.; Salvatella, L.
Angew. Chem., Int. Ed. 2005, 44, 458e461.
14. For C1-symmetric Phebox (non-macrocyclic), see: Ohshima, T.; Kawabata, T.;
Takeuchi, Y.; Kakinuma, T.; Iwasaki, T.; Yonezawa, T.; Murakami, H.; Nishiyama,
H.; Mashima, K. Angew. Chem., Int. Ed. 2011, 50, 6296e6300.
15. For recent examples of C1-symmetric Box ligands with different bridging
groups (non-macrocyclic), see: (a) McManus, H. A.; Cozzi, P. G.; Guiry, P. J. Adv.
Synth. Catal. 2006, 348, 551e558; (b) Atodiresei, I.; Schiffers, I.; Bolm, C. Tet-
rahedron: Asymmetry 2006, 17, 620e633; (c) McManus, H. A.; Cozzi, P. G.; Guiry,
P. J. Org. Biomol. Chem. 2007, 5, 763e766; (d) Hargaden, G. C.; O’Sullivan, T. P.;
Guiry, P. J. Org. Biomol. Chem. 2008, 6, 562e566; (e) Coeffard, V.; Aylward, M.;
Guiry, P. J. Angew. Chem., Int. Ed. 2009, 48, 9152e9155; (f) Liu, L.; Zhao, Q.; Du, F.;
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Acknowledgements
ꢁ
tillo, M. R.; Castillon, S.; Claver, C.; Fraile, J. M.; Gual, A.; Martín, M.; Mayoral, J.
A.; Sola, E. Tetrahedron 2011, 67, 5402e5408; (h) Liu, L.; Ma, H.; Fu, B. Molecules
2012, 17, 1992e1999; (i) Qu, J. P.; Liang, Y.; Xu, H.; Sun, X.-L.; Yu, Z.-X.; Tang, Y.
Chem.dEur. J. 2012, 18, 2196e2201.
We would like to thank EPSRC (EP/G006695/1) funding and the
EPSRC Mass Spectrometry services at Swansea for analytical
support.
16. Goldup, S. M.; Leigh, D. A.; McBurney, R. T.; McGonigal, P. R.; Plant, A. Chem. Sci.
2010, 1, 383e386.
17. For general CadioteChodkiewicz reaction see: (a) Cadiot, P.; Chodkiewicz, W. In
Chemistry of Acetylenes; Viehe, H. G., Ed.; Dekker: New York, NY, 1969;
pp 597e647; (b) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.
Ed. 2000, 39, 2632e2657.
Supplementary data
18. For general oxidative Heck reaction see: (a) Du, X.; Suguro, M.; Hirabayashi, K.;
Mori, A. Org. Lett. 2001, 3, 3313e3316; (b) McDonald, R. I.; Liu, G.; Stahl, S. S.
Chem. Rev. 2011, 111, 2981e3019.
19. For general CuAAC ‘click’ reaction see: (a) Kolb, H. C.; Finn, M. G.; Sharpless, K.
B. Angew. Chem., Int. Ed. 2001, 40, 2004e2021; (b) Meldal, M.; Tornøe, C. W.
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255, 2933e2945.
Supplementary data available: copies of 1H NMR and 13C NMR
spectra. Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2012.10.069.
20. For application of the CadioteChodkiewicz reaction in rotaxane and catenane
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