Synthesis and CD spectroscopy of polyethers with homochiral and heterochiral layers of stereocentres

Article abstract of DOI:10.1016/j.tet.2008.05.028

Eight polyethers with three to nine stereocentres have been synthesised using chiral base methodology. Examination of the polyethers by CD spectroscopy revealed clear differences between homochiral isomers and isomers with a heterochiral relationship betw

Full text of DOI:10.1016/j.tet.2008.05.028

Tetrahedron 64 (2008) 6615–6627
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and CD spectroscopy of polyethers with homochiral
and heterochiral layers of stereocentres
,
a
Alice R.E. Brewer c, Alex F. Drake b, Susan E. Gibson a , Jacob T. Rendell
*
a Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AY, UK
b Department of Pharmacy, Franklin Wilkins Building, King’s College London, London SE1 9NN, UK
c GDC NIBR, Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Eight polyethers with three to nine stereocentres have been synthesised using chiral base methodology.
Examination of the polyethers by CD spectroscopy revealed clear differences between homochiral iso-
mers and isomers with a heterochiral relationship between an ‘inner’ layer of stereocentres and an
‘outer’ layer of stereocentres. A hypothesis to account for these differences has been advanced.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 27 February 2008
Received in revised form 21 April 2008
Accepted 8 May 2008
Available online 11 May 2008
Keywords:
Asymmetric synthesis
CD spectroscopy
Chiral lithium amide base
Molecular architecture
1. Introduction
achiral branches, dendrimers with chiral peripheral surface groups
and dendrimers with chiral branching units.
A good understanding of how individual components of a large
molecular structure can be used to create and control its properties
is desirable, because it would facilitate more informed manipula-
tion and exploitation of macromolecules and supramolecular
structures in applications such as catalysis, drug delivery, molecular
recognition and light emitting and light harvesting processes.1–5
Dendritic-type molecules have for some time been considered good
models for disordered and semi-ordered structures such as poly-
mers, aggregates, clusters and liquid crystals, and they are now
starting to find applications of their own. For example, Dendritic
nanotechnologies have recently encapsulated both cisplatin and
carboplatin anticancer drugs in the voids of polyamidoamine
dendrimers.6 The dendrimer-drug conjugates are active against
aggressive tumour models, are water-soluble and have lower
toxicity and greater stability on storage than the unbound drugs.
Introduction of chirality into dendrimers increases their po-
tential structural diversity and future applications still further. A
wide range of dendritic structures has been explored in order to
probe the relationship between the chirality of the individual
elements and the properties of the global structure of the macro-
molecule.7,8 These include dendrimers with a chiral core and
Comparisons of dendritic molecules with a homochiral and
heterochiral relationship between layers, however, are rare. In one
example, Chow prepared a series of homochiral and heterochiral
layered tartrate-derived dendrimers including isomers 1 and 2
(Fig. 1), and compared them using CD spectroscopy.9,10 It was found
that the chiroptical effect of an
not exactly eliminate the effect of a
L
-chiral unit in the outer shell did
-chiral unit in the inner shell,
D
and it was concluded that the outer chiral layer was chiroptically
slightly different from the inner layer.
Later, Lellek examined the structural features of homochiral
dendrimer 3 and a heterochiral isomer 4 (Fig. 2), based on (R)- and
(S)-2,20-dimethoxy-1,10-binaphthalene building blocks.11 Differ-
ences between the homochiral and heterochiral isomers observed
in CD and NMR studies were explained by suggesting that the N–H
groups of the amides in the homochiral isomer form hydrogen
bonds that change the position of its conformational equilibria
relative to that of the heterochiral isomer.
We describe herein the synthesis of eight novel polyethers with
different relationships between the chirality at the centre of the
molecule (inner chirality) and at the edge (outer chirality). An in-
vestigation of the eight molecules by CD spectroscopy has revealed
that the homochiral and heterochiral isomers have significantly
different spectroscopic properties, and a hypothesis to account for
these differences is advanced. The synthesis of the four isomers of
16 (Schemes 2 and 4) and a brief discussion of their CD spectra have
been reported in a preliminary communication.12
* Corresponding author. Tel.: þ44 207 594 1140; fax: þ44 207 594 5804.
E-mail address: s.gibson@imperial.ac.uk (S.E. Gibson).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.028

6616
A.R.E. Brewer et al. / Tetrahedron 64 (2008) 6615–6627
O
O
L
L
L
L
L
L
O
O
ArO
ArO
D
L
O
O
L
L
L
L
D
D
L
L
OAr
O
OAr
O
L
L
O
O
O
O
O
O
O
O
O
O
O
O
O
O
ArO
ArO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OAr
OAr
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
ArO
ArO
OAr
OAr
1
2
Figure 1. Homo- and heterochiral dendrimers derived from tartaric acid.
O
O
R
O
HN
R
R
O
NH
R
O
O
H
N
R
HN
N
H
R
O
O
O O
O
O
O
O
R
HN
HN
O
O
R
R
R
H
N
O O
R
N
NH
O
H
R
O
O
O
HN
O
HN
O O
NH
O
O
O
O
3
HN
O
O
R
O
NH
R
HN
O O
NH
NH
R
O
O
O
S
H
N
O
HN
N
H
O O
O
R
O
NH
S
O
O
HN
S
O
O
O O
O
H
N
O
S
NH
N
R
H
R
R
O
O
R
HN
NH
O
4
O
O
O
Figure 2. Homo- and heterochiral dendrimers with axially chiral units.

A.R.E. Brewer et al. / Tetrahedron 64 (2008) 6615–6627
6617
OR
CO2Et
LiAlH4
(99%)
RO
TIPSO
CO2Et
OR
5
6
R = H
R = TIPS
TIPSCl
a) NaH
b) MeI
(97%)
7
8
R = H
imidazole
(99%)
R = Me
Cr(CO)6
(86%)
Ph
Ph
a)
OMe
OMe
NLi LiN
Ph
Ph
(OC)3Cr
TIPSO
(OC)3Cr
TIPSO
(S,R,R,S )-10
b) MeI
(77%)
OMe
OMe
9
(-)-11
air / light
(97%)
OMe
OMe
PPh3, CBr4
(91%)
RO
Br
OMe
(-)-12
(-)-13
OMe
R = TIPS
TBAF
(91%)
(-)-14
R = H
Scheme 1. Synthesis of the electrophile (ꢀ)-14.
2. Results and discussion
2.1. Synthesis
light promoted oxidative removal of the tricarbonylchromium(0)
unit from (ꢀ)-11 gave (ꢀ)-12 in excellent yield, leaving only the
conversion of the triisopropyl ether into a bromide necessary to
access the desired electrophile (ꢀ)-14. Initially the conversion from
(ꢀ)-12 to (ꢀ)-14 was attempted using a one-pot deprotection/
bromination procedure employing triphenylphosphine dibro-
mide,17 but this proved unsuccessful and a two step protocol was
adopted. Conversion of functionalised benzyl alcohols to bromides
is frequently achieved using triphenylphosphine and bromide. In
particular, Seebach reported this reaction in the presence of benzyl
ether groups and several other sensitive functionalities.18 Thus the
TIPS ether (ꢀ)-12 was deprotected to reveal the benzyl alcohol
(ꢀ)-13 by treatment with tetrabutylammonium fluoride. Bromi-
nation of the benzylic alcohol proceeded smoothly using the
Seebach procedure to give the desired electrophile (ꢀ)-14.
The readily available tricarbonylchromium(0) complex 1513,14
was deprotonated with 3 equiv of chiral base (S,R,R,S)- or (R,S,S,R)-
10, and bromide (ꢀ)-14 was added. After purification by column
chromatography, removal of the chromium(0) moiety by decom-
plexation in the presence of air and sunlight afforded the desired
homochiral and heterochiral isomers (Sinner,Souter)-16 and (Rinner,-
Souter)-16 (Scheme 2).
Our previous work on the use of chiral base chemistry to create
multiple stereocentres around an aromatic core with high levels of
stereochemical control,13,14 led us to predict that asymmetric
functionalisation of tris ether 15 (Scheme 2) with bromide (ꢀ)-14
(Scheme 1) would lead to the homochiral polyether (Sinner,Souter)-16
using chiral base (S,R,R,S)-10, and the heterochiral polyether
(RinnerSouter)-16 using chiral base (R,S,S,R)-10 (Scheme 2). The syn-
thesis of the required bromide (ꢀ)-14 is depicted in Scheme 1.
Initially, the hydroxyl group of commercially available diethyl 5-
(hydroxymethyl)isophthalate 5 was protected as the corresponding
triisopropylsilyl ether 6 in quantitative yield. This protecting group
was chosen due to its reported stability to a range of reducing
agents, as well as sodium hydride.15 The two ethyl ester groups
were subsequently reduced in the presence of the protected alcohol
with lithium aluminium hydride to give diol 7 as a white solid,
which was then converted into the diether 8. As chromium(0) is
known to insert into benzylic halide bonds even under mild con-
ditions,16 it was decided to form the chromium complex 9 prior to
converting the silyl ether into a bromide. The complexation pro-
ceeded smoothly to give 9, after which the two stereogenic centres
required at the periphery of target molecules 16 were installed in
100% de and 90% ee by deprotonation of 9 with 1.5 equiv of the
chiral base (S,R,R,S)-10 followed by an iodomethane quench. Air and
It was considered prudent at this stage of the project to syn-
thesise the enantiomers of (SinnerSouter)- and (RinnerSouter)-16 in
order to ascertain that these did indeed give the expected equal and
opposite CD traces. Accordingly, the bromide electrophile (þ)-14
was synthesised from chromium complex 9 (Scheme 3) and this

6618
A.R.E. Brewer et al. / Tetrahedron 64 (2008) 6615–6627
S
S
S
OMe
OMe
S
S
S
S
S
S
OMe
MeO
OMe
OMe
OMe
1a) (S,R,R,S)-10
MeO
(Sinner
b) (-)-14
2 air / light
(75%)
MeO
Souter)-16
OMe
OMe
(OC)3Cr
MeO
(RinnerSouter)-16
OMe
15
OMe
1a) (R,S,S,R)-10
b) (-)-14
2 air/ light
(86%)
OMe
MeO
OMe
OMe
MeO
OMe
MeO
S
S
R
R
R
S
S
S
S
Scheme 2. Synthesis of (SinnerSouter)- and (RinnerSouter)-16.
1a) (R,S,S,R)-10
R
R
OMe
OMe
b) MeI (68%)
2 air/light (98%)
3 TBAF (96%)
4 PPh3, CBr4 (85%)
(OC)3Cr
TIPSO
R
1a) (R,S,S,R)-10
b) (+)-14
2 air, light
(55%)
R
R
(RinnerRouter)-16
R
R
Br
OMe
R
R
OMe
(+)-14
9
Scheme 3. Synthesis of the electrophile (þ)-14.
OMe
OMe
(OC)3Cr
MeO
was used with the two enantiomers of the chiral base to produce
polyethers (RinnerRouter)- and (SinnerRouter)-16 (Scheme 4) [the
difference in yields probably reflects the smaller scale used for the
reaction that gives (SinnerRouter)-16]. The four stereoisomers of 16
were characterised by mp, IR spectroscopy, 1H NMR and 13C NMR
spectroscopy, mass spectrometry and elemental analysis. It is
worthy of note at this point that the 13C NMR spectra of the di-
astereoisomers of 16 were very similar in CDCl3, and that the 1H
NMR spectra of the two diastereoisomers were very similar to each
other in CDCl3, benzene and acetonitrile at room temperature, and
in methanol over the range 183–333 K.
15
R
R
1a) (S,R,R,R)-10
b) (+)-14
2 air,light
(32%)
S
(SinnerRouter)-16
S
S
R
R
R
R
Scheme 4. Synthesis of (RinnerRouter)- and (SinnerRouter)-16.

A.R.E. Brewer et al. / Tetrahedron 64 (2008) 6615–6627
6619
In order to investigate the effect of removing the peripheral chiral
OH
OBn
a) NaH
centres from polyethers 16, as monitored by CD spectroscopy,
molecules (Sinner)-19 and (Rinner)-19 (Scheme 6) were synthesised
next. Their synthesis required an achiral electrophile, which was
readily obtained by removal of the silyl protecting group from 8 to
give monoalcohol 17, followed by bromination to give benzyl
bromide 18 (Scheme 5).
(OC)3Cr
HO
(OC)3Cr
BnO
b) PhCH2Br
(81%)
OH
OBn
20
21
Scheme 7. Synthesis of the benzyl ether core 21.
OMe
OMe
Reaction of the new core with each of the enantiomers of the
chiral base 10 followed by quenching with the chiral electrophile
(þ)-14 gave the target molecules (SinnerRouter)- and (RinnerRouter)-22
(Scheme 8).
PPh3, CBr4
(79%)
RO
Br
OMe
R = TIPS
OMe
8
2.2. CD spectroscopy
TBAF
(88%)
18
17 R = H
Scheme 5. Synthesis of achiral electrophile 18.
As the isomers of 16 had given very similar NMR spectra in
a range of solvents, it was decided to examine them using the
relatively fast CD timescale to see if differences between the iso-
mers emerged. The UV and CD spectra of the four stereoisomers
(RinnerRouter)-16, (SinnerSouter)-16, (RinnerSouter)-16 and (SinnerRouter)-
16 are illustrated in Figure 3.
Reaction of core molecule 9 with each enantiomer of the chiral
base 10 followed by quenching with electrophile 18 gave (Sinner)-19
and (Rinner)-19 as required (Scheme 6).
All four isomers gave rise to identical UV spectra in which the
classical aryl chromophore was observed with the 1Lb transition at
260 nm, the 1La at 215 nm, and the degenerate 1Ea and 1Eb transi-
tions around 200 nm (Fig. 3, upper chart). The CD spectra differed,
however, particularly in the 1Lb region (Fig. 3, lower chart, 230–
280 nm). The CD in the 1Lb region is sensitive to the freedom of
rotation around the long axis of the aryl ring as this transition is
polarised across the short axis (see Fig. 4 for the definitions of short
and long axes). Thus the modest magnitude of the CD at 260–
275 nm observed for the heterochiral isomers (RinnerSouter)-16 and
(SinnerRouter)-16 is typical of an aryl group free to rotate or rock
about its long axis. The magnitude of the CD observed for the
homochiral isomers (RinnerRouter)-16 and (SinnerSouter)-16 in this
region, however, is exceptionally large (>10 times the magnitude
generally observed for aryl groups in chiral environments20), sug-
gesting that rotation about the long axis is severely restricted in
these isomers.
Figure 4 defines the electronic transition dipole moments of the
peripheral aryl groups in (SinnerSouter)-16. The solid arrow indicates
the dipole moment associated with the 1La and 1Eb bands, which
are found at lower wavelength (180–230 nm) in the chart in Fig-
ure 3. A basic premise of exciton coupling theory is that two elec-
tronic transition dipoles, which ideally are degenerate, couple to
produce a bisignate feature with a longer wavelength (lower
energy) CD sign that effectively defines the chirality of the two
interacting moments. Accordingly the bisignate couplet, which
changes sign at 198 nm for the heterochiral isomers and 203 nm for
the homochiral isomers (Fig. 3) is interpreted as a signature of
a ‘helical’ arrangement of the three pendant aryl groups in all four
isomers. Inspection of the four spectra illustrated in Figure 3 reveals
that the helices formed by the pendant chromophores are de-
pendent on the chirality of the core template (the inner chirality)
and not the chirality of the peripheral groupings (the outer
chirality).
OMe
OMe
S
S
S
OMe
MeO
OMe
OMe
MeO
OMe
MeO
(Sinner)-19
1a) (S,R,R,S)-10
b) 18
2 air / light
(30%)
OMe
OMe
(OC)3Cr
MeO
(Rinner)-19
OMe
9
OMe
1a) (R,S,S,R)-10
b) 18
OMe
2 air / light
(45%)
MeO
OMe
OMe
MeO
OMe
MeO
R
R
R
Scheme 6. Synthesis of (Sinner)-19 and (Rinner)-19.
In order to probe the effect of introducing greater steric bulk into
what appeared to be cavities in molecules 16, and at the same time
enhance the opportunities for aromatic–aromatic interactions, it
was decided to study molecules (SinnerRouter)- and (RinnerRouter)-22
(Scheme 8) inwhich the core methyl ethers have been replaced with
benzyl ethers. Their synthesis required the tris benzyl ether 21,
which was duly synthesised from the readily available tri-
carbonyl[1,3,5-tris(hydroxymethyl)benzene]chromium(0) 2019 by
a multiple deprotonation using sodium hydride followed by
quenching with benzyl bromide (Scheme 7).
The UV and CD spectra of the enantiomeric pair of molecules
lacking chirality at their periphery [(Rinner)-19] and (Sinner)-19] are
illustrated in Figure 5. The presence of the bisignate feature of the
CD spectra at lower wavelength is indicative of helical structure
once again, and comparison with the spectra of the isomers of 19 in
Figure 3 reveals that in 16 and 19 the S core leads to the same
handedness manifested by signals that go from negative to positive
with increasing wavelength. Interestingly the higher wavelength
bands of 19 are intermediate in intensity between those observed
for the isomers of 16.

6620
A.R.E. Brewer et al. / Tetrahedron 64 (2008) 6615–6627
R
R
OMe
OMe
S
R
S
S
R
OBn
R
R
BnO
OMe
OMe
MeO
OBn
MeO
(Sinner
1a) (S,R,R,S)-10
b) (+)-14
air/light
(45%)
2
R
outer)-22
OBn
(OC)3Cr
BnO
OBn
(RinnerRouter)-22
OMe
21
OMe
1a) (R,S,S,R)-10
b) (+)-14
2 air/light
(52%)
OBn
BnO
R
R
OMe
OMe
MeO
OBn
MeO
R
R
R
R
R
R
R
Scheme 8. Synthesis of (SinnerRouter)- and (RinnerRouter)-22.
25
20
15
10
5
CD spectra, and once again the handedness of the helix is governed
by the inner chiral centres. The higher wavelength features of the
CD spectra are remarkably similar to those observed for the methyl
ether diastereoisomers (Fig. 3), suggesting that the secondary
structures defined by the CD spectra are very similar despite the
significant difference between their inner ether groups.
25
20
15
10
5
Although it is clear from the above discussion that the homo-
chiral and heterochiral isomers of 16 and 22 present significantly
different CD spectra, a closer examination of the spectra of 16
revealed a further difference. Inspection of the spectra depicted in
Figure 4 revealed that although the UV absorption spectra of the
homo- and heterochiral compounds are virtually superimposable,
the vibronic structures in the CD spectra are notably different. The
first CD component in the heterochiral stereoisomers is at 275.5 nm
(36,297 cmꢀ1), whilst the first feature in the homochiral stereo-
isomer is at 273.8 nm (36,521 cmꢀ1) (Fig. 7). This difference
(224 cmꢀ1) implies that the homochiral stereoisomer CD is based
upon a false vibronic origin and confirms that the origin of the
optical activity is different for the homo- and heterochiral isomers.
Finally, a variable temperature study of the homochiral isomer
(SinnerSouter)-16 and heterochiral isomer (RinnerSouter)-16 was per-
formed using a 5:2:5 (v/v/v) mixture of ether, ethanol and iso-
pentane as the solvent. The spectrum of the homochiral isomer
(SinnerSouter)-16 remained essentially unchanged throughout (Fig. 8,
charts A and B). In contrast the heterochiral isomer (RinnerSouter)-16
showed dramatic changes at around ꢀ130 ꢁC, associated with ag-
gregation (Fig. 8, charts C and D). The UV became severely distorted
0
0
100
5
4
80
3
60
2
40
1
20
0
0
-1
-2
-3
-4
-5
-20
-40
-60
-80
-100
180
200
220
240
Wavelength (nm)
260
280
300
Figure 3. The UV spectra of 16 (upper chart) and the CD spectra of (RinnerRouter)-16
), (SinnerSouter)-16 ( ), (RinnerSouter)-16 ( ) and (SinnerRouter)-16 ( ) (lower chart).
(NB: The LH y axes correspond to the x axis range 180–230 nm and the RH y axes
correspond to the x axis range 230–300 nm.)
(
The UV and CD spectra of the diastereoisomeric pair of mole-
cules 22, which have benzyl ethers rather than methyl ethers as-
sociated with their inner chiral centres are shown in Figure 6. Once
again the bisignate feature is observed at lower wavelength in the

A.R.E. Brewer et al. / Tetrahedron 64 (2008) 6615–6627
6621
OMe
OMe
OMe
(SinnerSouter)-16
MeO
OMe
OMe
OMe
1La
dipole moment associatedwith the
(along long axis of aryl group)
and1Eb bands
dipole moment
associated
with the
MeO
1Lb and 1Ea
bands
MeO
(along
short axis
of aryl group)
Figure 4. Relationship between UV and CD bands and dipole moments of (SinnerSouter)-16.
25
20
15
10
5
12
10
8
6
4
2
0
3
25
20
15
10
5
0
0
5
100
4
80
3
60
2
2
40
1
1
20
0
0
0
-1
-2
-3
-4
-5
-20
-40
-60
-80
-100
-1
-2
-3
180
200
220
240
Wavelength (nm)
260
280
300
42000
40000 38000
Wavenumbers (cm-1)
36000
Figure 5. The UV spectra of 19 (upper chart) and the CD spectra of (Rinner)-19 (
),
Figure 7. UV spectra of 16 (upper chart) and the CD spectra of (RinnerRouter)-16 (
),
(Sinner)-19 (
) (lower chart).
(SinnerSouter)-16 (
), (RinnerSouter)-16 ( ) and (SinnerRouter)-16 ( ) (lower chart) with
the x axis in cmꢀ1
.
25
20
15
10
5
25
20
15
10
5
3. Conclusion
Chiral base chemistry has been used to construct dendritic-type
molecules with control over two layers of stereocentres. Although
the NMR spectra of molecules with homochiral layers and hetero-
chiral layers were very similar, their CD spectra revealed several
significant differences. For example the CD spectra in the range
240–280 nm gave much higher D3 values for the homochiral iso-
mers than the heterochiral isomers (Figs. 3 and 6) suggesting that
the aryl rings of the homochiral isomers are more restricted than
the aryl rings of the heterochiral isomers in their movement about
their long axis. Closer examination of this area of the spectrum
revealed that the vibronic structures in the CD spectra were notably
different (Fig. 7). Moreover, the behaviour of homochiral and het-
erochiral isomers on cooling was significantly different (Fig. 8) with
the heterochiral isomer displaying behaviour typical of a chiral
supramolecular structure at temperatures around ꢀ130 ꢁC.
The CD spectra of all the isomers of 16, 19 and 22 also presented
clear evidence for a helical arrangement of aryls, the handedness of
which was controlled by the inner layer of stereocentres. Moreover,
a comparison of Figures 3 and 6 depicting the spectra of isomers of
16 and 22 suggested that the substitution of the inner methyl
ethers with benzyl ethers had essentially no effect on the CD
behaviour of the molecules.
0
0
100
5
4
80
3
60
2
40
1
20
0
0
-1
-2
-3
-4
-5
-20
-40
-60
-80
-100
180
200
220
240
Wavelength (nm)
260
280
300
Figure 6. The UV spectra of 22 (upper chart) and the CD spectra of (RinnerRouter)-22
) and (SinnerRouter)-22 ( ) (lower chart).
(
and the CD spectrum showed an enhanced signal at 240–275 nm
and a significant negative feature at 325 nm. The latter is typical of
a chiral supramolecular structure of the sort normally associated
with condensed nucleic acids.21

6622
A.R.E. Brewer et al. / Tetrahedron 64 (2008) 6615–6627
6
5
4
3
2
1
6
5
4
3
2
1
A
C
0
5
0
5
B
D
4
3
4
3
2
2
1
1
0
0
-1
-2
-3
-4
-5
-1
-2
-3
-4
-5
240
260
280
Wavelength (nm)
300
320
340
240
260
280
300
Wavelength (nm)
320
340
Figure 8. The UV spectra of (SinnerSouter)-16 (chart A) and the CD spectra of (SinnerSouter)-16 (chart B) at 20 ꢁC ( ), ꢀ100 ꢁC ( ), ꢀ120 ꢁC ( ), and ꢀ137 ꢁC ( ), and the UV spectra of
(RinnerSouter)-16 (chart C) and the CD spectra of (RinnerSouter)-16 (chart D) at 20 ꢁC ( ), ꢀ100 ꢁC ( ), and ꢀ130 ꢁC (
).
OMe
A working hypothesis for the observations described above is
proposed as follows. In order for the relationship of the two layers
of stereocentres to have a significant effect on the conformational
equilibria of the molecules, it is most likely that the molecules
adopt condensed rather than extended conformations. It is postu-
lated that the molecule is drawn into condensed conformations
such as the one shown in Figure 9 by favourable aromatic–aromatic
interactions.22 It is postulated that in the homochiral isomer the
balance between energy lowering aromatic–aromatic interactions
H
MeO
H
OMe
H
CH3
H3C
H3C
R
H
R
H
R
and energy raising steric interactions between the atoms around
the outer chiral centres favours tighter conformations, whilst in the
heterochiral molecules the steric interactions become more dom-
inant and favour a more relaxed set of conformations that allow
more freedom of movement around the long axes of the aromatic
rings that make up the helix. It is of note that this picture of the
molecules is consistent with the almost identical behaviour of the
isomers of the methyl and benzyl ethers 16 and 22 in their CD
spectra, as it places these ethers towards the periphery of the
MeO
OMe
MeO
Figure 9. A representation of (RinnerRouter)-16, which would lead to interplay between
inner and outer chirality (for clarity one of the CH(CH3)OMe groups on each of the
outer aryl rings has been replaced by R).
molecule rather than within the interior of the structure as sug-
gested by the extended representations used in the description of
their synthesis. This working hypothesis will be tested and refined

A.R.E. Brewer et al. / Tetrahedron 64 (2008) 6615–6627
6623
in the future by the construction and analysis of molecules bearing
functional groups that can be used to rigidify it through, for ex-
ample, hydrogen bonding.
20 min. The flask was saturated with nitrogen and dry THF (75 mL)
was added. The resulting slurry was cooled to 0 ꢁC and a solution of
diethyl 5-(triisopropylsilyloxymethyl)isophthalate
6
(4.27 g,
10.5 mmol) in THF (75 mL) was added via a cannula. Subsequently,
the reaction mixture was allowed to reach rt and then stirred at
70 ꢁC for 15 h. After cooling to rt, the suspension was carefully
quenched with water (10 mL) and filtered through a pad of CeliteÒ,
which was washed with CHCl3 (300 mL). Solvents were removed
under reduced pressure to afford the title compound 7 (3.440 g,
99%) as a clear oil, which solidified into a white wax on standing.
Rf¼0.24 (SiO2; CHCl3/MeOH 9.5:0.5); mp 53–55 ꢁC; IR (nmax, DCM):
4. Experimental
4.1. General
All reactions and manipulations involving organometallic
compounds were performed under an inert atmosphere of dry ni-
trogen, using standard vacuum line Schlenk techniques.23 Flasks
were saturated with nitrogen using at least three evacuate/fill
cycles. Reactions and operations involving the use of (arene)-
tricarbonylchromium(0) complexes were protected from light. THF
was distilled over sodium benzophenone and used immediately.
DCM was distilled from calcium hydride. Tricarbonyl(1,3,5-trime-
thoxymethylbenzene)chromium(0) 1514 and tricarbonyl(1,3,5-
trihydroxymethylbenzene)chromium(0) 2019 were prepared
according to literature procedures. The concentration of n-butyl-
lithium was determined by titration against diphenylacetic acid in
THF.24 All other chemicals were used as purchased from commer-
cial sources. Thin layer chromatography (TLC) was performed on
Merck silica gel glass plates 60 (F254), using UV light (254 nm) as
visualising agent and/or vanillin or potassium permanganate as
developing agents. Flash column chromatography was performed
3603 (O–H), 1107 (C–O), 1067 (Si–O–C) cmꢀ1 1H NMR (400 MHz,
;
CDCl3):
d
¼1.12 (d, J¼6.6 Hz, 18H; CH(CH3)2), 1.18–1.23 (m, 3H;
CH(CH3)2), 1.90 (br t, J¼5.7 Hz, 2H; CH2OH), 4.71 (br d, J¼5.7 Hz, 4H;
CH2OH), 4.86 (s, 2H; CH2OSi), 7.29 (s, 2H; CArH), 7.30 (s, 1H;
C
ArH) ppm; 13C NMR (100 MHz, CDCl3):
d¼12.0 (CH), 18.1 (CH3),
64.8, 65.3 (CH2), 123.7, 124.0 (CArH), 141.2, 142.5 (CAr) ppm; MS (CI):
m/z (%): 342 (100) [MþNHþ4 ]; elemental analysis (%) calcd for
C18H32O3Si (324.53): C 66.62, H 9.94; found: C 66.53, H 9.78.
4.1.3. 1-(Triisopropylsilyloxymethyl)-3,5-dimethoxymethyl-
benzene 8
To a stirred and cooled (0 ꢁC) suspension of sodium hydride (60%
dispersion in mineral oil) (0.604 g,15.1 mmol, 2.6 equiv), previously
washed with hexane (5 mL), in THF (30 mL), was added a solution
of 1-(triisopropylsilyloxymethyl)-3,5-dihydroxymethylbenzene 7
(1.890 g, 5.8 mmol) in THF (10 mL) via a cannula. The reaction mix-
ture was allowed to warm to rt and was then stirred at 70 ꢁC for
75 min. After cooling to rt, iodomethane (1.44 mL, 23.2 mmol,
4.0 equiv) was added in one portion via a syringe. Stirring was
continued for 16 h. A saturated aqueous solution of NH4Cl (10 mL)
was added, the organic phase was separated and the aqueous phase
extracted with DCM (3ꢂ40 mL). The combined organic layers were
washed with brine (100 mL), dried (MgSO4) and concentrated in
vacuo. The crude oil was filtered through a pad of silica gel to afford
the title compound 8 (1.990 g, 97%) as a pale yellow oil. Rf¼0.48
using BDH silica gel (particle size 33–70 mm).
Melting points were recorded on a Sanyo Gallenkamp melting
point apparatus in open capillaries and are uncorrected. Optical
rotations were recorded on an AA 10 polarimeter from Index In-
struments, using a 1 dm path length and concentrations are given
as g dLꢀ1. IR spectra were recorded on a Perkin Elmer Spectrum RX
FT-IR spectrometer. NMR spectra were recorded at room temper-
ature on Bruker AC 300F, DRX 400, AV 400 or AV 500 instruments in
CDCl3, unless otherwise stated. J values are reported in hertz and
chemical shifts in parts per million. Mass spectra were recorded on
Micromass Platform II and Micromass AutoSpec-Q instruments by
the mass spectrometry service at Imperial College London. Ele-
mental analyses were performed by the London Metropolitan
University microanalytical service.
(SiO2; hexane/EtOAc 9:1); IR (nmax, DCM): 1105 (C–O–C) cmꢀ1
NMR (400 MHz, CDCl3):
;
1H
d
¼1.09 (d, J¼6.6 Hz, 18H; CH(CH3)2), 1.13–
1.22 (br m, 3H; CH(CH3)2), 3.38 (s, 6H; OCH3), 4.46 (s, 4H; CH2OCH3),
4.84 (s, 2H; CH2OSi), 7.19 (s, 1H; CArH), 7.26 (s, 2H; CArH) ppm; 13C
4.1.1. Diethyl 5-(triisopropylsilyloxymethyl)isophthalate 6
NMR (100 MHz, CDCl3):
d
¼12.0 (CH), 18.0, 58.1 (CH3), 64.8, 74.6
A solution of diethyl 5-(hydroxymethyl)isophthalate 5 (1.010 g,
4.0 mmol), imidazole (0.545 g, 8.0 mmol, 2.0 equiv) and triisopro-
pylsilyl chloride (0.94 mL, 4.4 mmol, 1.1 equiv) in dry DCM (12 mL)
was stirred at rt under an inert atmosphere for 16 h. The reaction
mixture was diluted with DCM (20 mL), washed with water
(2ꢂ15 mL), then brine (20 mL), dried (MgSO4), filtered and evapo-
rated under reduced pressure. The resulting opaque oil was purified
by flash column chromatography on silica gel (hexane/EtOAc 99:1/
95:5) to afford the title compound 6 (1.620 g, 99%) as a colourless oil.
Rf¼0.42 (SiO2; hexane/EtOAc 9:1); IR (nmax, DCM): 1724 (C]O),1237,
1116 (C–O–C ester),1029 (Si–O–C) cmꢀ1; 1H NMR (400 MHz, CDCl3):
(CH2), 124.4, 125.5 (CArH), 138.3, 142.1 (CAr) ppm; MS (CI): m/z (%):
370 (100) [MþNHþ4 ], 196 (51) [Mþꢀ(iPr)3SiþH]; elemental analysis
(%) calcd for C20H36O3Si (352.58): C 68.13, H 10.29; found: C 68.03, H
10.19.
4.1.4. Tricarbonyl[1-(triisopropylsilyloxymethyl)-3,5-
dimethoxymethylbenzene]chromium(0) 9
A dry 250 mL RB flask fitted with a water condenser was charged
with 1-(triisopropylsilyloxymethyl)-3,5-dimethoxymethylbenzene
8
(2.120 g, 6.0 mmol), hexacarbonylchromium(0) (1.320 g,
6.0 mmol), dry di-n-butyl ether (91 mL) and dry THF (9 mL). The
stirred suspension was protected from light and thoroughly satu-
rated with nitrogen, before heating it to 135 ꢁC. After 42 h, the
resulting yellow reaction mixture was allowed to cool to rt and
filtered through a pad of CeliteÒ to remove any oxidised chromium.
The filtrate was concentrated and the crude product purified by
flash column chromatography on silica gel (hexane/EtOAc, 98:2/
95:5) to afford the desired complex 9 as a yellow oil (2.530 g, 86%).
Rf¼0.48 (SiO2; hexane/EtOAc 8:2); IR (nmax, DCM): 1966, 1888
d
¼1.13 (d, J¼6.6 Hz, 18H; CH(CH3)2), 1.18–1.25 (m, 3H; CH(CH3)2),
1.43 (t, J¼7.2 Hz, 6H; CO2CH2CH3), 4.42 (q, J¼7.2 Hz, 4H;
CO2CH2CH3), 4.95 (s, 2H; CH2OSi), 8.26 (s, 2H; CArH), 8.59 (s, 1H;
C
ArH) ppm; 13C NMR (100 MHz, CDCl3):
d¼12.0 (CH(CH3)2), 14.3
(OCH2CH3), 18.0 (CH(CH3)2), 61.3 (OCH2CH3), 64.2 (CH2OSi), 125.4
(CArCO2Et),129.1,130.9 (CArH),142.7 (CArCH2OSi),166.0 (C]O) ppm;
MS (FABþ): m/z (%): 409 (71) [MþþH], 363 (76) [MþꢀEtO], 321 (50)
[Mþꢀ2EtO], 235 (100) [Mþꢀ2EtOꢀ2iPr]; elemental analysis (%)
calcd for C22H36O5Si (408.60): C 64.67, H 8.88; found: C 64.60, H 8.69.
(2ꢂC^O), 1110 (C–O–C) cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d¼1.12
(d, J¼6.2, 18H; CH(CH3)2), 1.16–1.22 (m, 3H; CH(CH3)2), 3.49 (s, 6H;
4.1.2. 1-(Triisopropylsilyloxymethyl)-3,5-dihydroxy-
methylbenzene 7
A 50 mL RB flask was charged with lithium aluminium hydride
(0.873 g, 23.0 mmol, 2.2 equiv) and placed under vacuum for
OCH3), 4.26 (s, 4H; CH2OCH3), 4.66 (s, 2H; CH2OSi), 5.33 (s, 1H;
C
ArH), 5.40 (s, 2H; CArH) ppm; 13C NMR (100 MHz, CDCl3):
d¼11.9
(CH), 18.0 (CH3), 59.0 (OCH3), 63.4, 73.0 (CH2), 88.8, 90.1 (CArH),
107.5, 112.3 (CAr), 232.6 (CO) ppm; MS (EI): m/z (%): 488 (45) [Mþ],

6624
A.R.E. Brewer et al. / Tetrahedron 64 (2008) 6615–6627
i
404 (87) [Mþꢀ3CO], 361 (100) [Mþꢀ3COꢀ Pr]; elemental analysis
(%) calcd for C23H36CrO6Si (488.61): C 56.54, H 7.43; found: C 56.35,
H 7.40.
1H NMR (400 MHz, CDCl3):
1.18–1.23 (m, 3H; SiCH(CH3)2), 1.46 (d, J¼6.5 Hz, 6H; CHCH3), 3.25
(s, 6H; OCH3), 4.33 (q, J¼6.5, 2H; CHCH3), 4.88 (s, 2H; CH2OSi), 7.14
(s, 1H; CArH), 7.22 (s, 2H; CArH) ppm; 13C NMR (126 MHz, CDCl3):
d
¼1.11 (d, J¼6.6 Hz, 18H; SiCH(CH3)2),
4.1.5. (ꢀ)- and (þ)-Tricarbonyl[1,3-bis(1-methoxyethyl)-5-
d
¼12.0 (SiCH(CH3)2), 18.0 (SiCH(CH3)2), 23.7 (CHCH3), 56.4 (OCH3),
(triisopropylsilyloxymethyl)benzene]-chromium(0) (ꢀ)- and (þ)-11
n-Butyllithium (4.15 mL, 2.24 M, 9.30 mmol, solution in hexanes,
3.0 equiv) was added dropwise to a stirred solution of the diamine
corresponding to diamide (S,R,R,S)-10 (1.95 g, 4.65 mmol, 1.5 equiv)
in THF (32 mL) at ꢀ78 ꢁC. The solution was allowed to warm to rt
over a period of 30 min to aid the formation of a bislithium amide.
The resulting deep purple solution was then re-cooled to ꢀ78 ꢁC
before a solution of heat gun dried lithium chloride (0.197 g,
4.65 mmol, 1.5 equiv) in THF (10 mL) was added via a cannula. The
reaction mixturewas stirred for a further 10 min before a pre-cooled
(ꢀ78 ꢁC) solution of complex 9 (1.52 g, 3.10 mmol, 1.0 equiv) in THF
(20 mL) was introduced dropwise via a short cannula. Stirring was
continued at ꢀ78 ꢁC for 60 min before iodomethane (1.16 mL,
18.6 mmol, 6.0 equiv) was added in one portion via a syringe. The
resulting yellow solution was then stirred until the reaction was
judged complete by TLC (75 min). The reaction was quenched with
MeOH (3 mL) and the solvent was removed in vacuo. The resulting
yellow residue was then dissolved in DCM, the diamine was re-
moved from the product mixture by an HCl (12 mL,1.0 M) wash, and
the aqueous phase extracted with DCM (24 mL). The extract was
dried (MgSO4), filtered and evaporated under reduced pressure.
Purification by flash column chromatography on silica gel (hexane/
Et2O, 96:4) afforded (ꢀ)-11 as a yellow oil. The enantiomeric purity
was determined by HPLC analysis (Chiralcel OD; n-hexane/iPrOH
99.5:0.5, 0.2 mL minꢀ1, 330 nm); (ꢀ)-enantiomer: tR¼26.4 min;
(þ)-enantiomer: tR¼28.3 min.
65.0 (CH2), 79.6 (CHCH3), 122.5 (CArH), 122.8 (CArH), 142.1, 143.6
(CAr) ppm; MS (CI): m/z (%): 398 (100) [MþNHþ4 ], 366 (28)
[MþꢀCH3þH], 224 (81) [MþꢀSi(iPr)3]; elemental analysis (%) calcd
for C22H40O3Si (380.64): C 69.42, H 10.59; found: C 69.52, H 10.53.
24
(þ)-12: Yield¼0.932 g, 98%. [
a]
þ84 (c 1.64, DCM); elemental
D
analysis (%) calcd for C22H40O3Si (380.64): C 69.42, H 10.59; found:
C 69.63, H 10.55; all other data were identical to that obtained for
(ꢀ)-12.
4.1.7. (ꢀ)- and (þ)-1,3-Bis(1-methoxyethyl)-5-
(hydroxymethyl)benzene (ꢀ)-13 and (þ)-13
To a solution of (ꢀ)-1,3-bis(1-methoxyethyl)-5-(triisopropylsi-
lyloxymethyl)benzene (ꢀ)-12 (0.188 g, 0.49 mmol, 1.0 equiv) in dry
THF (3.3 mL) was added tetrabutylammonium fluoride (0.98 mL,
1 M in THF, 2 equiv) dropwise via a syringe. The resulting pale
yellow mixture was stirred under an inert atmosphere for 3.5 h
before any remaining unreacted tetrabutylammonium fluoride was
quenched by addition of a saturated aqueous solution of NH4Cl
(3.3 mL). The layers were separated and the aqueous phase was
washed with DCM (3ꢂ3.3 mL). The organic phases were combined,
dried (MgSO4) and evaporated under reduced pressure. Purification
by flash column chromatography on silica gel (hexane/EtOAc
80:20/70:30) afforded the title compound (ꢀ)-13 as a colourless
oil, which solidified to form a white solid on standing.
The procedure for (ꢀ)-13 was repeated using 2.40 mmol
(0.920 g) of complex (þ)-12 to provide (þ)-13.
The procedure for (ꢀ)-11 was repeated using the diamine cor-
(ꢀ)-13: Yield¼0.100 g, 91%. Rf¼0.33 (SiO2; hexane/EtOAc 1:1);
24
responding to diamide (R,S,S,R)-10 and 1.47 mmol (0.720 g) of
mp 66–67 ꢁC; [
a]
ꢀ142 (c 0.118, DCM); IR (nmax, DCM): 3603 (O–
D
complex 9 to provide (þ)-11.
H), 1114, 1064 (C–O–C) cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
¼1.46 (d,
24
(ꢀ)-11: Yield¼1.230 g, 77%. [
a
]
ꢀ41 (c 1.16, DCM); HPLC
J¼6.5 Hz, 6H; CHCH3), 1.74 (s, 1H; OH), 3.26 (s, 6H; OCH3), 4.34 (q,
D
analysis: 90% ee. Rf¼0.37 (SiO2; hexane/EtOAc 9:1); IR (nmax, DCM):
J¼6.5, 2H; CHCH3), 4.74 (s, 2H; CH2OH), 7.21 (s, 1H; CArH), 7.29 (s,
1963, 1885 (2ꢂC^O), 1116 (C–O–C) cmꢀ1
;
1H NMR (400 MHz,
2H; CArH) ppm; 13C NMR (100 MHz, CDCl3):
d¼23.7 (CHCH3), 56.5
CDCl3):
d
¼1.11–1.18 (dþm, J¼6.2 Hz, 21H; iPr), 1.45 (d, J¼3.1 Hz, 3H;
(OCH3), 65.3 (CH2), 79.6 (CHCH3), 123.3 (CArH), 129.6 (CArH), 141.4,
144.2 (CAr) ppm; MS (EI): m/z (%): 224 (6) [Mþ], 209 (100)
[MþꢀCH3]; elemental analysis (%) calcd for C13H20O3 (224.3): C
CHCH3), 1.46 (d, J¼3.1 Hz, 3H; CHCH3), 3.49 (s, 6H; OCH3), 4.10–4.13
(m, 2H; CHCH3), 4.61 (s, 2H; CH2OSi), 5.41 (s, 2H; CArH), 5.58 (s, 1H;
C
ArH) ppm; 13C NMR (100 MHz, CDCl3):
d
¼11.9 (CH(CH3)2), 18.0
69.61, H 8.99; found: C 69.56, H 9.03.
24
(CH(CH3)2), 22.5 (CHCH3), 57.5 (OCH3), 63.5 (CH2), 76.9 (CHCH3),
88.2, 88.6, 89.3 (CArH), 110.6, 112.4 (CAr), 233.1 (CO) ppm; MS (EI):
m/z (%): 516 (11) [Mþ], 432 (19) [Mþꢀ3CO], 349 (27)
[Mþꢀ3COꢀOCH3ꢀCr], 145 (100) [Mþꢀ3COꢀ2OCH3ꢀCrꢀOSi(iPr)3];
elemental analysis (%) calcd for C25H40CrO6Si (516.66): C 58.12, H
(þ)-13: Yield¼0.519 g, 96%. [
a]
þ141 (c 1.24, DCM); elemental
D
analysis (%) calcd for C13H20O3 (224.3): C 69.61, H 8.99; found: C
69.54, H 9.09; all other data were identical to that obtained for
(ꢀ)-13.
7.80; found: C 58.30, H 7.70.
4.1.8. (ꢀ)- and (þ)-1,3-Bis(1-methoxyethyl)-5-
(bromomethyl)benzene (ꢀ)- and (þ)-14
24
(þ)-11: Yield¼0.520 g, 68%. [
a
]
þ41 (c 1.15, DCM); HPLC
D
analysis: 88% ee; elemental analysis (%) calcd for C25H40CrO6Si
(516.66): C 58.12, H 7.80; found: C 58.20, H 7.76; all other data were
identical to that obtained for (ꢀ)-11.
To
a
solution of (ꢀ)-1,3-bis(1-methoxyethyl)-5-(hydroxy-
methyl)benzene (ꢀ)-13 (0.535 g, 2.4 mmol, 1.0 equiv) in dry THF
(48 mL) was added triphenylphosphine (0.944 g, 3.6 mmol,
1.5 equiv). The reaction mixture was stirred for 5 min and then
carbon tetrabromide (1.19 g 3.6 mmol, 1.5 equiv) was added, which
eventually resulted in the formation of a white precipitate. The
reaction mixture was saturated with nitrogen and the reaction was
stirred at rt under an inert atmosphere in the dark until it was
deemed complete by TLC (1.5 h). The mixture was then filtered and
the precipitate was washed with dry THF. Evaporation of the filtrate
and purification by flash column chromatography on silica gel
(hexane/EtOAc 95:5/90:10) afforded the desired bromide (ꢀ)-14
as a colourless oil.
4.1.6. (ꢀ)- and (þ)-1,3-Bis(1-methoxyethyl)-5-
(triisopropylsilyloxymethyl)benzene (ꢀ)- and (þ)-12
The dialkylated complex (ꢀ)-11 (0.325 g, 0.63 mmol) was dis-
solved in dry DCM (30 mL) and the solution was thoroughly satu-
rated with air. The reaction mixture was stirred in an open vessel at
rt in direct sunlight until the reaction was complete by TLC (22 h).
The crude green product mixture was filtered through a pad of
CeliteÒ and neutral alumina, the pad was thoroughly washed with
dry Et2O and the filtrate was concentrated under reduced pressure
to afford the product as a colourless oil.
The procedure for (ꢀ)-14 was repeated using 2.3 mmol (0.514 g)
The procedure for (ꢀ)-12 was repeated using 2.50 mmol
of complex (ꢀ)-13 to provide (þ)-14.
24
(1.290 g) of complex (þ)-11 to provide (þ)-12.
(ꢀ)-14: Yield¼0.630 g, 91%. [
a
]
ꢀ109 (c 1.55, DCM); IR (nmax
,
D
24
(ꢀ)-12: Yield¼0.233 g, 97%. [
a
]
ꢀ82 (c 1.58, DCM); Rf¼0.32
DCM): 1115, 1097 (C–O–C), 568 (C–Br) cmꢀ1
;
1H NMR (500 MHz,
D
(SiO2; hexane/EtOAc 9:1); IR (nmax, neat film): 1115 (C–O–C) cmꢀ1
;
CDCl3):
d¼1.43 (d, J¼6.5 Hz, 6H; CHCH3), 3.24 (s, 6H; OCH3), 4.30 (q,

A.R.E. Brewer et al. / Tetrahedron 64 (2008) 6615–6627
6625
J¼6.5, 2H; CHCH3), 4.50 (s, 2H; CH2Br), 7.17 (t, J¼1.5 Hz, 1H; CArH),
7.25 (d, J¼1.5 Hz, 2H; CArH) ppm; 13C NMR (126 MHz, CDCl3):
5.1 Hz, 3H; CHCHH), 7.00 (s, 6H; CArH), 7.04 (s, 3H; CArH), 7.08 (s,
3H; CArH) ppm; 13C NMR (126 MHz, CDCl3):
(CH2), 56.4, 56.8 (OCH3), 79.5, 84.7 (CH), 121.8, 124.2, 126.2 (CArH),
138.9,142.1,143.5 (CAr) ppm; MS (ESI): m/z (%): 852 (100) [MþþNa];
elemental analysis (%) calcd for C51H72O9 (829.11): C 73.88, H 8.75;
found: C 73.87, H 8.68.
(SinnerRouter)-16: Yield¼0.056 g, 32%. Mp 84–86 ꢁC; elemental
analysis (%) calcd for C51H72O9 (829.11): C 73.88, H 8.75; found: C
73.89, H 8.96; all other analytical data were identical to that of
(RinnerSouter)-16.
d¼23.7 (CH3), 44.6
d
¼23.7 (CHCH3), 33.5 (CH2), 56.6 (OCH3), 79.3 (CHCH3), 124.0, 125.9
(CArH), 138.2, 144.6 (CAr) ppm; MS (EI): m/z (%): 288 (10) [Mþ], 286
(10) [Mþ], 273 (98) [MþꢀCH3], 271 (100) [MþꢀCH3], 207 (42)
[MþꢀBr]. HRMS (EI): m/z(%) calcd for C13H19BrO2: 288.0548,
286.0568, found: 288.0545 [Mþ], 286.0569 [Mþ].
24
(þ)-14: Yield¼0.561 g, 85%. [
a]
þ110 (c 1.07, DCM); all other
D
data collected was identical to that obtained for (ꢀ)-14.
4.1.9. (SinnerSouter)-16, (RinnerRouter)-16, (RinnerSouter)-16 and
(SinnerRouter)-16
4.1.10. 1,3-Bis(methoxymethyl)-5-(hydroxymethyl)benzene 17
n-Butyllithium (0.72 mL, 1.80 mmol, 2.50 M in hexanes,
6.0 equiv) was added dropwise to a stirred solution of the diamine
corresponding to diamide (S,R,R,S)-10 (0.378 g, 0.90 mmol,
3.0 equiv) in THF (18 mL) at ꢀ78 ꢁC. The solution was allowed to
warm to rt over a period of 30 min. The resulting deep purple so-
lution was then re-cooled to ꢀ78 ꢁC before a solution of heat gun
dried lithium chloride (0.038 g, 0.90 mmol, 3.0 equiv) in THF (2 mL)
was added via a cannula. The reaction mixture was stirred for
a further 10 min before a pre-cooled (ꢀ78 ꢁC) solution of complex
15 (0.104 g, 0.30 mmol, 1.0 equiv) in THF (3 mL) was introduced
dropwise via a short cannula. Stirring of the resulting orange
mixture was continued at ꢀ78 ꢁC for 1 h before a solution of bro-
mide electrophile (ꢀ)-14 (0.327 g, 1.10 mmol, 3.8 equiv) in THF
(7 mL) was added via a short cannula. The resulting yellow solution
was then stirred until the reaction was judged complete by TLC
(5 h). The reaction was quenched with MeOH (2 mL) and the sol-
vent was removed in vacuo. Purification of the yellow residue by
flash column chromatography on silica gel (hexane/Et2O, 100:0–
60:40) afforded the desired chromium complex. This was then
dissolved in dry DCM (15 mL) and the yellow solution was saturated
with air. The reaction mixture was stirred in an open vessel at rt in
direct sunlight until the reaction was complete (20 h). The crude
green product mixture was filtered through a Pasteur pipette
containing a plug of CeliteÒ and neutral alumina, the filter plug was
rinsed with dry Et2O and the filtrate was evaporated to afford the
product (SinnerSouter)-16 as a white solid.
To a solution of 1-(triisopropylsilyloxymethyl)-3,5-dimethoxy-
methylbenzene 8 (1.560 g, 4.4 mmol) in dry THF (29 mL) was added
tetrabutylammonium fluoride (8.85 mL, 8.8 mmol, 1.0 M, 2.0 equiv)
dropwise via a syringe. The resulting pale yellow mixture was
stirred under an inert atmosphere for 3 h before any remaining
unreacted tetrabutylammonium fluoride was quenched by addition
of a saturated aqueous solution of NH4Cl (10 mL). The layers were
separated and the aqueous phase was washed with DCM
(3ꢂ20 mL). The organic phases were combined, dried (MgSO4) and
evaporated under reduced pressure. Purification by flash column
chromatography on silica gel (hexane/EtOAc 70:20/50:50) affor-
ded the desired product as a pale yellow oil (0.758 g, 88%). Rf¼0.22
(SiO2; hexane/EtOAc 1:1); IR (nmax, neat film): 3417 (O–H), 1098 (C–
O) cmꢀ1; 1H NMR (400 MHz, CDCl3):
6H; OCH3), 4.48 (s, 4H; CH2OCH3), 4.71 (s, 2H; CH2OH), 7.29 (s, 1H;
ArH), 7.30 (s, 2H; CArH) ppm; 13C NMR (100 MHz, CDCl3):
d¼1.92 (br s, 1H; OH), 3.42 (s,
C
d
¼58.3
(CH3), 65.1, 74.5 (CH2), 125.5, 126.2 (CArH), 138.8, 141.4 (CAr) ppm;
MS (EI): m/z (%): 196 (78) [Mþ], 165 (100) [MþꢀOCH3]; elemental
analysis (%) calcd for C11H16O3 (196.24): C 67.32, H 8.22; found: C
67.26, H 8.27.
4.1.11. 1,3-Bis(methoxymethyl)-5-(bromomethyl)benzene 18
To
a
solution of 1,3-bis(methoxymethyl)-5-(hydroxy-
methyl)benzene 17 (0.741 g, 3.8 mmol) in dry THF (76 mL) was
added triphenylphosphine (1.490 g, 5.7 mmol, 1.5 equiv). The re-
action mixture was stirred for 5 min and then carbon tetrabromide
(1.880 g, 5.7 mmol, 1.5 equiv) was added, which eventually resulted
in the formation of a white precipitate. The reaction mixture was
saturated with nitrogen and the reaction was stirred at rt under an
inert atmosphere in the dark until judged complete by TLC
(90 min). The mixture was filtered and the precipitate was washed
with dry THF. Evaporation of the filtrate and purification by flash
column chromatography on silica gel (hexane/EtOAc 95:5/90:10)
afforded the desired bromide as a colourless oil (0.780 g, 79%).
Rf¼0.80 (SiO2; hexane/EtOAc 1:1); IR (nmax, DCM): 1101 (C–O–C),
The procedure for (SinnerSouter)-16 was repeated using (a) the
diamine corresponding to diamide (R,S,S,R)-10 and the electrophile
(þ)-14 on 0.27 mmol (0.094 g) of complex 15 to provide (Rinner
-
Router)-16; (b) the diamine corresponding to diamide (R,S,S,R)-10
and the electrophile (ꢀ)-14 on 0.27 mmol (0.096 g) of complex 15
to provide (RinnerSouter)-16 and (c) the diamine corresponding to
diamide (S,R,R,S)-10 and the electrophile (þ)-14 on 0.20 mmol
(0.068 g) of complex 15 to provide (SinnerRouter)-16.
(SinnerSouter)-16: Yield¼0.185 g, 75%. Mp 84–85 ꢁC; IR (nmax
,
DCM): 1114,1099 (C–O–C) cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
¼1.39
563 (C–Br) cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
¼3.43 (s, 6H; OCH3),
4.48 (s, 4H; CH2OCH3), 4.52 (s, 2H; CH2Br), 7.29 (s, 1H; CArH), 7.33 (s,
2H; CArH) ppm; 13C NMR (100 MHz, CDCl3):
(d, J¼6.5 Hz, 18H; CH3), 2.82 (dd, J¼14.0, 5.0 Hz, 3H; CHCHH), 3.04
(dd, J¼14.0, 8.5 Hz, 3H; CHCHH), 3.13 (s, 9H; inner OCH3), 3.20 (s,
18H; outer OCH3), 4.24 (q, J¼6.5 Hz, 6H; CHCH3), 4.31 (dd, J¼8.5,
5.0 Hz, 3H; CHCHH), 7.01 (s, 6H; CArH), 7.04 (s, 3H; CArH), 7.08 (s,
d
¼33.3 (CH2), 58.4
(CH3), 74.2 (CH2), 126.8, 127.5 (CArH), 138.1, 139.2 (CAr) ppm; MS
(EI): m/z (%): 260 (43) [Mþ], 258 (49) [Mþ], 229 (60) [MþꢀOCH3],
227 (66) [MþꢀOCH3], 179 (100) [MþꢀBr]; elemental analysis (%)
calcd for C11H15BrO4 (259.14): C 50.98, H 5.83; found: C 51.06,
H 5.90.
3H; CArH) ppm; 13C NMR (126 MHz, CDCl3):
d
¼23.7 (CH3), 44.7
(CH2), 56.4, 56.8 (OCH3), 79.5, 84.8 (CH), 122.0, 124.2, 126.2 (CArH),
139.0, 142.2, 143.5 (CAr) ppm; MS (ESI): m/z (%): 852 (100)
[MþþNa]; elemental analysis (%) calcd for C51H72O9 (829.11): C
73.88, H 8.75; found: C 73.72, H 8.71.
4.1.12. (Sinner)-19, (Rinner)-19
(RinnerRouter)-16: Yield¼0.123 g, 55%. Mp 87–88 ꢁC; elemental
analysis (%) calcd for C51H72O9 (829.11): C 73.88, H 8.75; found: C
73.93, H 8.89; all other analytical data were identical to that of
(SinnerSouter)-16.
n-Butyllithium (1.28 mL, 1.80 mmol, 1.41 M in hexanes,
6.0 equiv) was added dropwise to a stirred solution of the diamine
corresponding to diamide (S,R,R,S)-10 (0.378 g, 0.90 mmol,
3.0 equiv) in THF (14 mL) at ꢀ78 ꢁC. The solution was allowed to
warm to rt over a period of 30 min to aid the formation of
a bislithium amide. The resulting deep purple solution was then re-
cooled to ꢀ78 ꢁC before a solution of heat gun dried lithium chlo-
ride (0.038 g, 0.90 mmol, 3.0 equiv) in THF (2 mL) was added via
a cannula. The reaction mixture was stirred for a further 15 min
(RinnerSouter)-16: Yield¼0.179 g, 86%. Mp 86.5–87.5 ꢁC; IR (nmax
,
DCM): 1114,1099 (C–O–C) cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
¼1.39
(d, J¼6.5 Hz, 18H; CH3), 2.82 (dd, J¼14.0, 5.1 Hz, 3H; CHCHH), 3.04
(dd, J¼14.0, 8.0 Hz, 3H; CHCHH), 3.12 (s, 9H; inner OCH3), 3.19 (s,
18H; outer OCH3), 4.24 (q, J¼6.5 Hz, 6H; CHCH3), 4.31 (dd, J¼8.0,

6626
A.R.E. Brewer et al. / Tetrahedron 64 (2008) 6615–6627
before a pre-cooled (ꢀ78 ꢁC) solution of complex 15 (0.104 g,
0.30 mmol, 1.0 equiv) in THF (5 mL) was introduced dropwise via
a short cannula. Stirring of the resulting orange mixture was
continued at ꢀ78 ꢁC for 60 min before a solution of 1,3-bis(me-
thoxymethyl)-5-(bromomethyl)benzene 18 (0.360 g, 1.39 mmol,
4.6 equiv) in THF (6 mL) was added via a short cannula. The
resulting yellow solution was then stirred until the reaction was
complete by TLC (2.5 h). The reaction was quenched with MeOH
(2 mL) and the solvent was removed in vacuo. Purification of the
yellow residue by flash column chromatography on silica gel
(hexane/Et2O, 100:0/0:100) afforded the desired trisfunctional-
ised chromium complex. The complex (0.078 g, 0.09 mmol,
1.0 equiv) was dissolved in dry DCM (15 mL) and the yellow solu-
tion was saturated with air. The reaction mixture was stirred in an
open vessel at rt in direct sunlight until the reaction was complete
by TLC (48 h). The crude green product mixture was filtered
through a Pasteur pipette containing a plug of CeliteÒ and neutral
alumina, the filter plug was thoroughly rinsed with dry Et2O and
the filtrate was evaporated to dryness to afford the product (Sinner)-
19 as a colourless film.
(126 MHz, CDCl3):
d
¼70.3, 73.3 (CH2), 90.0 (CCrH), 108.0 (CCr), 127.9,
128.0, 128.5 (CArH), 137.4 (CAr), 232.5 (CO) ppm; MS (EI): m/z (%):
574 (14) [Mþ], 490 (100) [Mþꢀ3CO], 399 (6) [Mþꢀ3COꢀPhCH2];
elemental analysis (%) calcd for C33H30CrO6 (574.58): C 68.98, H
5.26; found: C 68.84, H 5.22.
4.1.14. (SinnerRouter)-22, (RinnerRouter)-22
n-Butyllithium (0.62 mL, 1.56 mmol, 2.50 M in hexanes,
6.0 equiv) was added dropwise to a stirred solution of the diamine
corresponding to diamide (S,R,R,S)-10 (0.328 g, 0.78 mmol,
3.0 equiv) in THF (12 mL) at ꢀ78 ꢁC. The solution was allowed to
warm to rt over a period of 30 min to aid the formation of
a bislithium amide. The resulting deep purple solution was then re-
cooled to ꢀ78 ꢁC before a solution of heat gun dried lithium chloride
(0.033 g, 0.78 mmol, 3.0 equiv) in THF (3 mL) was added through
a cannula. The reaction mixture was stirred for a further 10 min
before a pre-cooled (ꢀ78 ꢁC) solution of tricarbonyl[1,3,5-tris(ben-
zyloxymethyl)benzene]chromium(0) 21 (0.148 g, 0.26 mmol,
1.0 equiv) in THF (4 mL) was introduced dropwise via a short can-
nula. Stirring of the resulting orange mixture was continued at
ꢀ78 ꢁC for 60 min before a solution of (þ)-14 (0.309 g,1.08 mmol) in
THF (5 mL) was added via a short cannula. The resulting yellow
solution was then stirred until the reaction was complete (4 h). The
reaction was quenched with MeOH (2 mL) and the solvent was re-
moved in vacuo. Purification of the yellow residue by flash column
chromatography on silica gel (hexane/EtOAc 97:3/80:20) afforded
the desired trisfunctionalised chromium complex. This was dis-
solved in dry DCM (5 mL) and the yellow solution was saturated
with air. The reaction mixture was stirred in an open vessel at rt in
direct sunlight until the reaction was complete (48 h). The crude
green product mixture was filtered through a Pasteur pipette con-
taining a plug of CeliteÒ and neutral alumina, the filter plug was
thoroughly rinsed with dry Et2O and the filtrate was evaporated to
dryness to afford the desired product (SinnerRouter)-22 as a colourless
film.
The procedure for (Sinner)-19 was repeated using the amine
corresponding to (R,S,S,R)-10 on 0.31 mmol (0.108 g) of complex 15
to give (Rinner)-19.
(Sinner)-19: Yield (chiral base reaction)¼0.078 g, 30%; amount
used for decomplexation step¼0.078 g, 0.09 mmol; yield (decom-
plexation)¼0.076 g, 99%; 30% yield over 2 steps. IR (nmax, neat film):
1100 (C–O–C) cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
¼2.80 (dd, J¼13.8,
5.3 Hz, 3H; CHCHH), 3.02 (dd, J¼13.8, 8.0 Hz, 3H; CHCHH), 3.13 (s,
9H; inner OCH3), 3.36 (s, 18H; outer OCH3), 4.29 (dd, J¼8.0, 5.3 Hz,
3H; CHCHH), 4.39 (s, 12H; CH2O), 7.01 (s, 6H; CArH), 7.03 (s, 3H;
C
ArH), 7.12 (s, 3H; CArH) ppm; 13C NMR (126 MHz, CDCl3):
d¼44.6
(CHCH2), 56.7 (inner OCH3), 58.1 (outer OCH3), 74.5 (CH2O), 84.8
(CHCH2),124.3,124.9,128.0 (CArH),138.1,138.9,142.0 (CAr) ppm; MS
(ESI): m/z (%): 767 (100) [MþþNa]; elemental analysis (%) calcd for
C
45H60O9 (744.95): C 72.55, H 8.12; found: C 72.44, H 7.94.
(Rinner)-19: Yield (chiral base reaction)¼0.172 g, 63%; amount
The procedure for (SinnerRouter)-22 was repeated using the amine
corresponding to (R,S,S,R)-10 on 0.30 mmol (0.172 g) of complex 21
to give (RinnerRouter)-22. The column chromatography was per-
formed using (hexane/EtOAc 97:3/50:50).
used for decomplexation step¼0.143 g, 0.16 mmol; yield (decom-
plexation)¼0.086 g, 72%; 45% yield over 2 steps. Elemental analysis
(%) calcd for C45H60O9 (744.95): C 72.55, H 8.12; found: C, 72.61, H
8.13; all other data obtained were identical to that of (Sinner)-19.
(SinnerRouter)-22: Yield¼0.125 g, 45%. IR (nmax, DCM): 1114, 1097
(C–O–C) cmꢀ1
;
1H NMR (500 MHz, C6D6):
d
¼1.45 (d, J¼6.4 Hz,
4.1.13. Tricarbonyl[1,3,5-tris(benzyloxymethyl)-
benzene]chromium(0) 21
18H; CHCH3), 3.01 (dd, J¼13.8, 4.6 Hz, 3H; CHCHH), 3.11 (s,
18H; OCH3), 3.24 (dd, J¼13.8, 8.7 Hz, 3H; CHCHH), 4.15 (q,
J¼6.4 Hz, 6H; CHCH3), 4.22 (d, J¼12.4 Hz, 3H; OCHHPh), 4.52 (d,
J¼12.4 Hz, 3H; OCHHPh), 4.60 (dd, J¼8.7, 4.6 Hz, 3H; CHCHH), 7.04
(m, 3H; CArH), 7.12 (t, J¼7.5 Hz, 6H; CArH). 7.20 (d, J¼7.5 Hz, 6H;
To a stirred and cooled (0 ꢁC) suspension of sodium hydride (60%
dispersion in mineral oil, 0.480 g, 12.0 mmol, 4.0 equiv), previously
washed with hexane (5 mL), in THF (40 mL), was added a solution
of tricarbonyl[1,3,5-tris(hydroxymethyl)benzene]chromium(0) 20
(0.913 g, 3.0 mmol) in THF (20 mL) via a cannula. The reaction
mixture was allowed to warm to rt, a condenser was fitted to the
reaction vessel and the system was thoroughly saturated with ni-
trogen and stirred at 70 ꢁC for 2 h. After cooling to rt, the condenser
was replaced with a septum-containing adapter. The flask was
saturated with nitrogen and benzyl bromide (2.14 mL, 18.0 mmol,
6.0 equiv) was added in one portion via a syringe. The resulting
yellow/white mixture was protected from light and stirred over-
night at rt. A saturated aqueous solution of NH4Cl (20 mL) was
added, the organic phase was separated and the aqueous phase
extracted with DCM (3ꢂ60 mL). The combined organic layers were
washed with brine (120 mL), dried (MgSO4) and concentrated in
vacuo. The crude material was purified by flash column chroma-
tography on silica gel (hexane/EtOAc 100:0/65:35) to afford the
desired product (1.400 g, 81%) as a yellow solid. Rf¼0.51 (SiO2;
hexane/EtOAc 8:2); mp 78–80 ꢁC; IR (nmax, DCM): 1961, 1881
C
C
ArH), 7.23 (br s, 3H; CArH), 7.26 (br s, 6H; CArH), 7.37 (s, 3H;
ArH) ppm; 13C NMR (126 MHz, C6D6):
d
¼24.4 (CHCH3), 45.5
(CH2), 56.3 (OCH3), 70.7 (CH2Ph), 79.9 (CHCH3), 82.8 (CHCH2),
122.4, 125.0, 126.9, 127.6, 128.3, 128.5 (CArH), 139.1, 139.5, 143.3,
144.5 (CAr) ppm; MS (ESI): m/z (%): 1080 (100) [MþþNa]; ele-
mental analysis (%) calcd for C69H84O9 (1057.4): C 78.38, H 8.01;
found: C 78.51, H 7.92.
(RinnerRouter)-22: Yield¼0.162 g, 52%. IR (nmax, DCM): 1114, 1097
(C–O–C) cmꢀ1; 1H NMR (500 MHz, C6D6):
d
¼1.45 (d, J¼6.4 Hz, 18H;
CHCH3), 3.02 (dd, J¼13.8, 4.6 Hz, 3H; CHCHH), 3.13 (s, 18H; OCH3),
3.25 (dd, J¼13.8, 8.8 Hz, 3H; CHCHH), 4.15 (q, J¼6.4 Hz, 6H; CHCH3),
4.21 (d, J¼12.3 Hz, 3H; OCHHPh), 4.53 (d, J¼12.3 Hz, 3H; OCHHPh),
4.61 (dd, J¼8.8, 4.6 Hz, 3H; CHCHH), 7.05 (m, 3H; CArH), 7.13 (t,
J¼7.5 Hz, 6H; CArH). 7.19 (d, J¼7.5 Hz, 6H; CArH), 7.24 (br s, 3H;
C
ArH), 7.27 (br s, 6H; CArH), 7.39 (s, 3H; CArH) ppm; 13C NMR
(126 MHz, CDCl3):
d
¼24.4 (CHCH3), 45.6 (CH2), 56.3 (OCH3), 70.8
(CH2Ph), 79.9 (CHCH3), 82.8 (CHCH2), 122.4, 125.0, 126.8, 127.6,
128.5 (CArH), 139.1, 139.5, 143.4, 144.5 (CAr) ppm. MS (ESI): m/z (%):
1080 (100) [MþþNa]; elemental analysis (%) calcd for C69H84O9
(1057.4): C 78.38, H 8.01; found: C 78.29, H 7.90.
(2ꢂC^O), 1100 (C–O–C) cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
¼4.31
(s, 6H; CArCH2O), 4.65 (s, 6H; OCH2CAr), 5.36 (s, 3H; CArH), 7.30–7.35
(m, 3H; CArH), 7.37 (d, J¼4.4 Hz, 12H; CArH) ppm; 13C NMR

A.R.E. Brewer et al. / Tetrahedron 64 (2008) 6615–6627
6627
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Simultaneous UV and CD spectra were measured with a nitro-
gen-flushed Chirascan spectrometer.25 The solvent used for the
room temperature studies was CH3CN, and the path length was
1 cm in the near UV region (400–230 nm), and 0.5 mm in the far UV
region (230–180 nm). Sample concentrations were in the order of
0.5 mg/mL in the near UV region and 0.1 mg/mL in the far UV.
Spectra were accumulated with a 0.5 nm collection every 2 s.
For the variable temperature study, a Jasco J720 spectrometer
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measured directly with a thermocouple probe in the sample solu-
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normalised for concentration and path length to give
3 and D3.
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