Generating cis-aza-diaryl and triaryl ethers via organoBr?nsted acid catalysed aza-Darzens chemistry

Article abstract of DOI:10.1016/j.tet.2019.130532

We report the efficient combination of S_NAr and organic Br?nsted acid catalysis protocols for the construction of cis-aziridine-derived biaryl and triaryl ethers. Using aza-Darzens chemistry mono-cis-aziridine-biaryl and bis-(cis-aziridine)-triaryl ethers have been generated; these motifs have significant potential as easily synthesised, functionalised precursors of a glycopeptide backbone.

Full text of DOI:10.1016/j.tet.2019.130532

Tetrahedron 75 (2019) 130532
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Tetrahedron
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Generating cis-aza-diaryl and triaryl ethers via organoBrønsted acid
catalysed aza-Darzens chemistry
,
Sean P. Bew a *, Simon J. Coles b, Mateusz B. Pitak b, Wim T. Klooster b,
Polly-Anna Ashford a, Victor Zdorichenko a
a School of Chemistry, Norwich Research Park, UEA, Norwich, NR4 7TJ, UK
b UK National Crystallography Service, School of Chemistry, University of Southampton, Southampton, SO17 1BJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the efficient combination of SNAr and organic Brønsted acid catalysis protocols for the con-
struction of cis-aziridine-derived biaryl and triaryl ethers. Using aza-Darzens chemistry mono-cis-azir-
idine-biaryl and bis-(cis-aziridine)-triaryl ethers have been generated; these motifs have significant
potential as easily synthesised, functionalised precursors of a glycopeptide backbone.
© 2019 Published by Elsevier Ltd.
Received 14 May 2019
Received in revised form
30 July 2019
Accepted 14 August 2019
Available online 19 August 2019
As the Founder and Editor in Chief for Tet-
rahedron: Asymmetry we dedicate this pa-
per to Professor Stephen Davies with thanks
to his friendship, advice and outstanding
service to organic chemistry.
Keywords:
Catalysis
Organic Brønsted acid
Aziridine
Aza-Darzens
Glycopeptide
SNAr
1. Introduction
product. But, upon closer analysis this key motif presents numerous
synthesis challenges, which if its construction is incorporated at a
Glycopeptides such as vancomycin [1] [1, (X ¼ Cl, Fig. 1)] are
frontline antibiotic therapies with an intriguing and conserved
structural C-O-D-O-E ‘backbone’. Appended with two 16-
membered macrocycles it is equipped with C-O-D and D-O-E
biaryl ethers ‘stitched’ together via a heptapeptide chain. Triaryl
biether C-O-D-O-E motifs are critical components of these natural
products affording them with point chiral and atropisomeric ster-
eocenters, structure complexity and conformational rigidity. Thus,
synthetic routes affording glycopeptides require, at the outset,
innovative approaches to the construction of the triaryl C-O-D-O-E
motif. An initial assessment of this group suggests it should be
relatively straightforward to generate with pre-requisite function-
ality for subsequent transformations/incorporation into the natural
late-stage in the natural product synthesis can be problematic.
Interestingly, in all glycopeptide natural product syntheses to date
late-stage aryl ether construction was undertaken (with varying
degrees of success). For example, Terada and co-workers used toxic
thallium(III) nitrate to mediate an oxidative aryl ether cyclization
[3] (not shown) and, although 2 (Fig. 1) was generated in a 20%
yield, it was afforded with an inseparable and unidentified by-
product.
Pearson and co-workers exploited late-stage biaryl ether con-
struction using cyclopentadienyl ruthenium (CpRu) complexes as
photocleavable activators and SNAr chemistry. Here, cesium car-
bonate mediated an efficient intramolecular SNAr on 3 which, after
mild CpRu cleavage (UV irradiation), afforded 4 in a good overall
yield (Scheme 1) [4]. A number of strategies have been developed
for assembling the ‘halogen-free’ Orienticin C [2] [2 (X ¼ H, Fig. 1)
aglycone version] triaryl biether backbone. As similar as 1 is to 2 it
* Corresponding author.
E-mail address: s.bew@uea.ac.uk (S.P. Bew).
https://doi.org/10.1016/j.tet.2019.130532
0040-4020/© 2019 Published by Elsevier Ltd.

2
S.P. Bew et al. / Tetrahedron 75 (2019) 130532
ꢀ
derived from pyrrole 8, N-heterocyclic carbene 9 and PINTs. Jouille
and co-workers [8] developed a highly convergent route to Usti-
loxin F (15) via cyclopeptide precursor 14 (90% yield) using a cop-
per(I) acetate catalysed regio- and stereoselective ring-opening of
cis-aziridine 13 with phenol 12.
2. Overview
Organic Brønsted acid catalysis is, now, an indispensable ‘tool’ in
the synthetic chemists' ‘toolbox’. [9]. As part of an ongoing inves-
tigation developing simple, organic Brønsted acid catalysed routes
to important heterocycles we required an organocatalytic approach
to cis-aziridines equipped with biaryl or triaryl-ethers.
Our rac-aza-Darzens protocol uses an aldehyde, amine, alkyl
diazoacetate and pyridinium triflate; a cheap, ‘off the shelf’ catalyst
which readily affords structure and function diverse N-substituted
cis-C2,3-disubstituted rac-aziridines [10]. Similarly, using (S)-18,
optically active [11] cis-aziridines are afforded in excellent yields
and diastereoselectivites. We applied both protocols to a simple
natural product synthesis; thus, cis-16 was transformed into the
antibiotic (þ)-chloramphenicol (17, Scheme 3) in 3-steps and 41%
overall yield.
Fig. 1. Vancomycin aglycone 1 (X ¼ Cl) and Orienticin C aglycone 2 (X ¼ H).
Pearson et al.
Cl
RuCpPF6
OCH3
OCH3
OH
O
1. Cs2CO3, DMF, 0 °C
2. CH3CN, hv, 18 hrs
E
OTBS
O
OTBS
O
D
O
CH3
NBoc
O
CH3
NBoc
H
N
H
76% over 2 steps
N
N
H
N
H
N
H
N
H
O
O
CN
CN
4
3
Evans et al.
OAllyl
OH
NO2
OAllyl
F
O
O
O
1. CsF, DMF, 23 °C
2. BF3 OEt, t-BuONO
CH2Cl2, 0°C
E
OH
D
OH
O
O
O
CH3
NBoc
O
CH3
NBoc
H
H
HN
N
HN
N
N
H
N
H
3. Bu3SnH, THF, 23 °C
63% overall yield
N
H
N
H
O
O
O
O
O
O
6
DdmHN
DdmHN
5
Using our knowledge of organic Brønsted acid catalysed aza-
Darzens chemistry we envisaged an ‘early-stage’ construction of
cis-aziridine-derived biaryl and triaryl ethers. These, we imagine,
would serve as convenient staging posts en route to advanced
neoteric glycopeptide intermediates. In this study we outline:
F
Evans et al.
NO2
OAllyl
1. CsF, DMF, 23 °C (90%)
2. Zn, AcOH, EtOH, 40 °C
3. H3PO4, NaNO2, THF/H2O,
Cu2O, 0 °C (85% yield over 2-steps)
4. N2O4, NaOAc, 0 °C
5. H2O2, LiOH, (46% yield over 2-steps)
6. Pd(PPh3)4 (5 mol%), morpholine, THF, rt
7. 10% Pd/C, H2 100 psi, CH3OH
8. TFA, DMS, CH2Cl2, rt
Cl
O
OH
C
O
D
Cl
HO
O
O
OH
H
H
N
N
orienticin C
N
H
N
H
NH CH3
NBoc
2
HN
O
O
O
B
DmdHN
HO2C
O
A
OH
OH
a) Synthetic routes to strategic, regioselectively and orthogo-
nally functionalised C-O-D biaryl ether building blocks.
b) A synthetic route to an important regioselectively and
orthogonally functionalised C-O-D-O-E triaryl ether building
block.
HO
7
Scheme 1. SNAr synthesis of bi/triaryl macrocyclic ethers.
does exhibit one key difference which for our preliminary studies
was important; it lacks chiral atropisomerism on the C- and E-aryl
rings.
c) Single aza-Darzens cis-aziridination of a regioselectively
protected mono-aldehyde affording a biaryl cis-aziridine
derived C-O-D motif.
Previous syntheses of biaryl/triaryl ethers have exploited late-
stage cesium fluoride/SNAr chemistry. For example, Evans and co-
workers transformed halogen-free tetrapeptide 5 into macrocycle
6 (Scheme 1); exploiting this late-stage macrocyclic chemistry on
the more complex glycopeptide precursor 7 a similar cesium fluo-
ride mediated SNAr afforded, after successive manipulation
(Scheme 1), Orienticin C (2, Fig. 1) [5].
d) aza-Darzens cis-aziridination of a bis-aldehyde-derived tri-
aryl biether appended on the central aryl with an alkene or
an ester, see for example (cis-aziridine-C)-O-D-(C]C)eO-
(aldehyde-E) 19 (Q is a C]C, Scheme 4).
e) Asymmetric aminohydroxylation of a C]C appended to the
D ring a component of the C-O-D motif and subsequent
transformation of the
-amino acid.
a-amino alcohol into the prerequisite
Aziridines are highly versatile heterocycles used to generate
sought-after azasugars, b-lactams, polymers, a- and b-amino acids,
a
chiral auxiliaries and pyrrolidines [6]. They are also widely used key
intermediates en route to structure and function diverse natural
products. By way of example, Trost and co-workers [7] synthesised
(þ)-Agelastatin A 11 (Scheme 2) via N-tosyl cis-aziridine 10; itself
3. Results and discussion
Generating the prerequisite cis-aziridine-derived C-O-D-O-E
backbone (cf. 2) necessitated a straightforward synthesis of bis-
OCH3
tert-butyl
O
diazoacetate
H
N
O2N
H2N
CAN
CH3CN, H2O
OCH3
tert-butyl
(S)-18 (1 mol%)
H
H
O
diazoacetate
H
N
O2N
H2N
CAN
CH3CN, H2O
4Å MS, CHCl3
-60 °C, 24 hrs
OtBu
+
CO2tBu
(S)-18 (1 mol%)
4Å MS, CHCl3
-60 °C, 24 hrs
H
H
0 °C to rt
67% yield
OtBu
N
+
H
H
CO2tBu
OCH3
0 °C to rt
67% yield
N
H
H
CO2tBu
cis-16
99% yield
96% e.e.
O2N
OCH3
tBuO
CO2tBu
cis-16
99% yield
96% e.e.
O2N
tBuO
1. Cl2CHCO2H
O2N
1. Cl2CHCO2H
Anthracene
1,2-DCE
reflux, 1 hr
76% yield
O2N
Anthracene
1,2-DCE
reflux, 1 hr
76% yield
OH OH
O
OH OH
O
O
O
O
O
P
SO2CF3
2. NaBH4, CH3OH
0.5 hr, 0 °C
P
SO2CF3
N
2. NaBH4, CH3OH
0.5 hr, 0 °C
N
H
HN
CHCl2
H
HN
CHCl2
O2N
(+)-chloramphenicol, 17
79% yield
O2N
(+)-chloramphenicol, 17
79% yield
Anthracene
(S)-18
O
Anthracene
O
(S)-
18
Scheme 2. Use of cis-aziridines in natural product synthesis.
Scheme 3. Asymmetric aza-Darzens catalysed by (S)-18.

S.P. Bew et al. / Tetrahedron 75 (2019) 130532
3
Table 1
Solvent, temperature and time optimization for the synthesis of biaryl ether 23 and
triaryl biether 22.
Entry
Solvent
Temp
Time
Yield 23
Yield 22
1a
2a
3a
4a
5a
6a
7b
8c
9d
DMF
DMF
DMF
DMA
DMA
DMSO
DMSO
DMSO
DMSO
25 ꢀ
70 ꢀ
C
C
C
24 h
4 h
4 h
48 h
0.5 h
2 h
2 h
1 h
2 h
0%
0%
0%
0%
0%
0%
0%
5%
<5%
56%
<20%
<5%
20%
21%
<5%
32%
42%
21%
160 ꢀ
70 ꢀ
C
160 ꢀ
160 ꢀ
160 ꢀ
160 ꢀ
160 ꢀ
C
C
C
C
C
a
2.5eqn K2CO3.
b
c
2eqn Cs2CO3.
2.5eqn Cs2CO3.
3.2 eqn Cs2CO3.
Scheme 4. Functionalised biaryl and triaryl ethers.
d
aldehyde-derived triaryl biether 22 (Scheme 5). We envisaged
undertaking a double SNAr between methyl gallate 20 and 4-
fluorobenzaldehyde 21. At room temperature using DMF and
excess potassium carbonate (2.5 eqn) no reaction was observed
(Entry 1, Table 1). The same reaction at 70 ꢀC (oil bath) afforded 23
but in a poor yield and only after 48 h (Entry 2). Disappointingly,
attempts at increasing the yield by heating at 160 ꢀC afforded 1-(4-
dimethylamino)benzaldehyde (Entry 3). We presume this was
generated via an SNAr reaction between dimethylamine, a thermal
decomposition product of DMF, and 21. Negating this DMA and
microwave irradiation (160 ꢀC) afforded 23 in a 21% yield (Entry 5)
in only 30 min (cf. 48 h, oil bath). Gratifyingly, substituting cesium
carbonate for potassium carbonate in DMA increased the yield of
23e32% and triaryl biether 22 was observed for the first time albeit
in 5% yield (Entry 7). Finally, after reaction optimization using
DMSO and 3.2 equivalents of 21 at 160 ꢀC for 2 h, dialdehyde 22 was
obtained in a 56% yield which in conjunction with mono-aldehyde
(23) afforded a 77% overall yield (Entry 9).
The advantageous role of cesium carbonate was attributed to the
“cesium effect” [12]. Dipolar aprotic DMSO, DMA and DMF are able
to dissolve cesium salts affording homogeneous, dissociated free-
ions or solvent-separated ion-pairs. Thus, with cesium carbonate
a basic and ‘naked’ carbonate anion results which in conjunction
with the solvated and highly polarized Csþ (1.67 Å) facilitates a
considerably more efficient SNAr process.
Although microwave irradiation offered a fast and efficient route
to key building block 22 it was limited to 500 mg ‘batch’ syntheses.
Demonstrating the robust nature of the small-scale microwave
reaction it was adapted and developed into a protocol capable of
generating multigram quantities. Thus, using DMSO at 120 ꢀC
(aluminium heating block), 2.5 equivalents of 21 and a 48-h reac-
tion time 22 was afforded with minimal reduction in yield. With a
large quantity of impure 22/23 (2:1) in hand we were keen to purify
it avoiding the use of flash chromatography and large quantities of
solvent; gratifyingly, careful trituration of the impure mixture with
cold (0 ꢀC) diethyl ether selectively dissolved the more non-polar 22
leaving the majority of the more polar catechol 23 behind. Evapo-
rating the ether and repeating the process on semi-purified product
afforded nearly 9 g of 22 with an estimated (1H NMR) purity of 98%
(Scheme 5).
It was important to establish that the SNAr had afforded the
desired 3,5-triaryl ether 22 (cf. C-O-D-O-E backbone of 1 and 2) and
not the 3,4-regioisomer (not shown). A mechanistic rational sup-
porting 3,5-biaryl ether formation focused on the pKa differences of
the hydroxyls and the increased stability of the more acidic 4-
hydroxy phenol (pKa 8) which after deprotonation undergoes
ester conjugation generating a quinone-like species (not shown).
In contrast, deprotonating the less acidic 3-hydroxyphenol (pKa
12) affords a more reactive and less stabilized phenoxide which
efficiently reacts with 21 affording meta-aldehyde 23 and, subse-
quently, 3,5-bis-arylaldehyde 22. Conclusive evidence for 3,5-
dietherification was sought. Pale brown monoclinic crystals were
grown from ether and analysed via X-ray diffraction. These
confirmed 22 to be the symmetric 3,5-disubstituted triaryl biether.
In depth analysis of 22 established it had a non-planar conforma-
tion; the C and E aryl rings tilted at ~70ꢀ to the central D-ring (Fig. 2,
top right image). Curiously, this is comparable to the 80ꢀ ‘tilt’
identified in the crystal structure of the C-O-D-O-E part of
Scheme 5. SNAr reaction between 22 and 21 affording aldehyde-derived triaryl biether
22 and biaryl ether 23.
Fig. 2. X-ray crystal structure of 22. Dashed lines outline intra and intermolecular
hydrogen bonds. Numerical values outline bond lengths and dihedral bond angles.

4
S.P. Bew et al. / Tetrahedron 75 (2019) 130532
vancomycin (1, Fig. 1) [13]. Further analysis afforded substantive
evidence of an intermolecular 2.65 Å hydrogen bond between the
4-phenol hydroxyl on D (22) and a carbonyl lone-pair on a second
molecule of 22 ring E with a 118ꢀ OeH/O dihedral angle (Fig. 2,
lower image, right hand side). Moreover, an intramolecular
OeH/O hydrogen bond (dihedral angle 112ꢀ) was identified in 22
that formed a 5-membered ring between the 4-hydroxyl on D and
one of the lone pairs on the oxygen biaryl ether (Fig. 2, lower image,
top-middle).
Microfluidic reaction conditions confer many benefits e.g. less
reagent/solvent consumption, more controllable heat transfer,
better mixing and improved safety profiles e the latter is especially
important with reactive and or unstable species [14]. Incorporating
a flow synthesis regime (Uniqsis FlowSyn [15]), a static mixer and a
column packed with cesium carbonate we wanted to probe the
20% yield (Scheme 6, Path C).
Negating this a switch from an ‘acetal 1st - SNAr 2nd route, that
is 20 / 25 / 26 to a ‘SNAr 1st e acetal 2nd route i.e. 20 / 23 / 28
(Scheme 6) allowed biaryl catechol 23 to be transformed into diol-
protected mono-aldehyde 28 in a slightly improved yield (Scheme
6). Generating bis-4,5-O-benzyl ether 28 was straightforward.
Reacting 23 with benzyl bromide and potassium carbonate in DMF
at 120 ꢀC for 7 h afforded 28 in a 73% yield (Scheme 6); no evidence
of any mono-O-benzylated (not shown) adducts were found.
With the successful synthesis of 28 in hand we wanted to
generate a methyl ether on the 4-position of the ‘D-ring‘ of aza-
Darzens precursor 29. Reacting 23 with one equivalent each of
lithium carbonate and iodomethane in DMF 4-methyl ether 29 was
afforded in a 71% yield (Scheme 7). Confirming the regioselectivity
of the etherification was important. Commercially available methyl
3,5-dihydroxy-4-methoxybenzoate reacted (SNAr) with one equiv-
alent of 21 and cesium carbonate. The 1H and 13C NMR spectra of
this product matched those obtained from the 23 / 29 route
(Scheme 7).
Finally, orthogonal O-protection of 29 employed tert-butyldi-
phenylsilyl chloride (1.1 eqn) and imidazole (2.2 eqn) in DMF, TBDPS
ether 30 was obtained in an unoptimized 57% yield (Scheme 7). O-
Methyl and O-benzyl triaryl biether 31 and 39 were generated in an
excellent 92% (Scheme 7) and 87% yields respectively (Scheme 10).
With aldehyde 28 in hand our focus switched to its trans-
formation into the corresponding rac-aziridine 32 (Scheme 8).
Incorporating a one-pot, two-stage aziridination protocol the pre-
requisite imine was generated from 2-tert-butoxyaniline and,
without further purification or isolation, it was activated with
pyridinium triflate (10 mol%) and reacted with tert-butyl diazo-
acetate. After 12 h the reaction was judged complete, and the
product was purified via flash column chromatography. Mono-cis-
aziridine (C2,3 J 6.7 Hz) 32 was afforded in a 64% yield (Scheme 8).
mfluidic synthesis of 22 and 23 via the reaction of DMSO solutions of
20 and 21. Interestingly, despite numerous and widespread appli-
cations of SNAr chemistry its use in flow chemistry is, practically,
non-existent and no double SNAr reactions on a single substrate (cf.
20 / 22, Scheme 4) have been reported. Using excess cesium car-
bonate, relative to methyl gallate, it should be possible to increase
the reaction rate and efficiency of the SNAr biaryl ether coupling.
Pumping (1 mL/min) a 1.1 M DMSO solution of 20 and a 2.5 M so-
lution of fluorobenzaldehyde through a heated glass column
(150 ꢀC, 6.6 ꢁ 100 mm, packed with Cs2CO3) improved the yield and
rate of the SNAr reaction. The desired 22 and 23 (1:1) were gener-
ated in an improved 81% yield. Following trituration with cold ether
23 was selectively removed; this allowed 23 to be resubmitted to an
SNAr with 21. Using this protocol the overall yield of 22 was
increased to 91%.
Incorporating the bi- and triaryl ethers into an organocatalytic
Brønsted acid aza-Darzens reaction, our goal, ultimately, is to ring-
open the cis-aziridines and generate aryl ether derived
b-hydroxy-
a
-amino acids. Initiating this aspect of our work required an O-
Future studies required an optically active
installed on the central D-aryl ring (38, Scheme 9). This, we
envisaged, could be accomplished via a Sharpless asymmetric
a-amino acid be
methyl, O-benzyl ether, or a 4-methoxybenzylidine acetal pro-
tected methyl gallate e.g. 25 (Scheme 6) [16] which we hoped to
transform into 4-benzoxy-3,4-dihydroxybenzoate methyl ester
(not shown). Transacetalisation of methyl gallate with 24 (4 Å MS,
0.5 mol% PTSA) in toluene at reflux afforded cyclic acetal 25
(Scheme 5). Disappointingly, attempts at mediating an SNAr with 21
using the reagents, conditions, and solvents in Table 1 were, by and
large, low yielding (Scheme 6, Path A). Changing tack an Ullman
etherification using 25, 4-bromobenzaldehyde (27), copper(II) ox-
ide, potassium carbonate and pyridine (Scheme 6, Path B) was also
unsuccessful; no reaction was observed and the starting materials
were returned in good yield. Finally, 21 and 25 did react via an SNAr
at 75 ꢀC in acetonitrile but the product (26) was afforded in a poor
a
-
aminohydroxylation and, subsequent, alcohol oxidation. Initiating a
model study, 3-(4,4’,5,5’)-tetramethyl-1,3-dioxolan-2-yl)phenol 33
was coupled to 3-bromobenzaldehyde via a procedure reported by
Buchwald and co-workers that used 10 mol% copper(I) iodide and
20 mol% 1,10-phenanthroline in pyridine (120 ꢀC); 34 was afforded
in a 67% yield. Wittig chemistry transformed meta-aldehyde-
derived biaryl ether 34 into styrene 35 (Scheme 9) in an excellent
95% yield, whilst its oxidation employed a mixture of benzyl
carbamate, (DHQ)2PHAL (6 mol%), potassium osmate (4 mol%) and
tert-butyl hypochlorite. The desired a-amino alcohol 36 was affor-
ded with an excellent 96% e.e. (Phenomenex Lux cellulose-1).
Subsequent oxidation of the 1ꢀ alcohol using TEMPO, sodium hy-
pochlorite and 10 mol% sodium bromide generated carboxylic acid
37 in an 87% yield which, after esterification (CH3I, K2CO3, DMF),
was hydrogenated using 10% Pd/C affording 1ꢀ amine 38 in an 88%
O
OCH3
Path C
OCH3
OCH3
24
CHO
O
O
20
Toluene, pTSA
reflux, 3 hrs
41% yield
21, Cs2CO3
O
O
O
O
MeCN
HO
Ph
Si
O
75 °C, 72 hrs
tBu
Ph
OCH3
OCH3
Path A
26
CO2CH3
CH3I
Li2CO3, DMF
20% yield
imidazole
HO
O
21, K2CO3, DMA
µW, 80 - 160 °C, 3 hrs
O
TBDMS- Cl
25
23
CO2CH3
H
Path B
rt, 18 hrs
57% yield
55 °C, 18 hrs
71% yield
H
51
4-bromobenzaldehyde (27)
CO2CH3
29
O
(Low yielding)
Cu(II)O, K2CO3,
CO2CH3
30
O
23
pyridine, reflux, 16 hrs
24
31 (No reaction)
X
toluene, 120 °C
OH
OCH3
CH3I
K2CO3
OBn
BnBr
pTSA (0.5 mol%)
O
O
O
O
26
K2CO3, DMF
BnO
O
28% yield
DMF
80 °C, 18 hrs
92% yield
OHC
CHO
120 °C, 7 hrs
73% yield
OHC
CHO
H
CO2CH3
22
CO2CH3
31
CO2CH3
O
28
Scheme 6. Synthetic routes to biaryl-mono-aldehyde 26 and 28 from starting mate-
rials 23 and 25.
Scheme 7. Synthesis of orthogonally O-protected biaryl ether 30 from catechol 29 and
O-methylation of triaryl ether 22 generating bis-aldehyde 31.

S.P. Bew et al. / Tetrahedron 75 (2019) 130532
5
OBn
1. 2-tert-butoxyaniline
Although it is feasible the cis-aziridine in 41 impacts the dia-
stereoselectivity of the second aza-Darzens reaction its influence,
over 15 atoms, is likely to be minimal and certainly not predictable.
Nevertheless we wanted to use X-ray diffraction to determine the
relationship between the cis-aziridines in 40. Disappointingly, all
attempts at obtaining crystals suitable for X-ray diffraction failed,
with either ‘gummy’ or amorphous solids formed. Thus, at the
present time it is not possible to assign if bis-cis-aziridine 40 has
meso- or C2-symmetry. Additional studies are ongoing which aim
to clarify this and will, in due course, be reported.
OBn
4Å molecular sieves, rt BnO
O
BnO
O
CO2tBu
OtBu
2. tert-butyl diazoacetate
pyridinium triflate
CH2Cl2, -30 °C
64% yield
H
N
CO2CH3
CO2CH3
O
32
28
Scheme 8. One-pot, two-step synthesis of cis-aza-biaryl ether 32 from bis-4,5-O-
benzyl biaryl ether aldehyde 28.
O
10 mol% CuI
20 mol%
It was important to demonstrate the ‘core’ triaryl biether D-ring
was, similar to biaryl aldehyde 34 (Scheme 9), suited to alkene
synthesis and, presumably, thereafter amenable to asymmetric a-
CHO
O
O
O
1,10-phenanthroline
1.5 eqn K2CO3
pyridine, 120 °C, 5 hrs
67% yield
O
+
O
Br
34
CH3P(C6H5)3Br
amino hydroxylation. Clearly, chemoselective reduction of the ester
in 39 would likely fail, with the more reactive aldehydes being
reduced in preference. Negating this acetal 42 was synthesised (86%
yield) from 39 using Dean-Stark conditions, pinacol and 0.5 mol% of
PTSA,23 following this the ester was reduced with lithium
aluminium hydride in an excellent 97% yield. Oxidation of the 1ꢀ
alcohol using excess activated manganese (II) dioxide afforded
aldehyde 43 in a 69% yield. A small monoclinic crystal of 43 was
submitted to X-ray diffraction [18]; this confirmed the presence of
both pinacols, the aldehyde and the benzyl ether. Aldehyde 43
underwent a Wittig reaction using two equivalents of sodium hy-
dride and an equimolar amount of methyltriphenylphosphonium
bromide affording vinyl-44 (Scheme 11) in a 51% yield. The slightly
lower yield and reaction rate (cf. 35, Scheme 8) was attributed to
the lower reaction temperature and equivalents of Wittig reagent
used. Conducting the reaction at 0 ꢀC, whilst increasing the equiv-
alents of Wittig reagent from two to three afforded 44 in an
improved 76% yield (Scheme 11).
OH
NaH, THF
0 °C, 30 min
95% yield
33
3 eq NaOH
3 eq CbzNH2
3 eq tert-butyl hypochhlorite
6 mol% (DHQD)2PHAL
4 mol% K2OsO2(OH)4
n-PrOH / H2O (2 : 1)
O
O
O
O
O
O
NHCbz
36
0 °C, 3 hrs
65% yield, 96% e.e.
OH
35
1.1 eq TEMPO
3 eq NaOCl
10 mol% NaBr
acetone / NaHCO3
0 °C, 3 hrs
87% yield
1. CH3I, K2CO3,
DMF, 0 °C, 3 hrs
O
O
E
D
O
O
O
2. H2 / 10% Pd H3CO
2 hrs, 50 psi
88% yield
O
HO
NH2
38
NHCbz
37
O
O
Scheme 9. Asymmetric synthesis of biaryl ether derived
methyl ester 38.
a-aryl
a
-amino carboxylate
In contrast to methyl acetals the sterically hindered pinacol
acetals are more challenging to cleave; often requiring elevated
temperature and stronger, aqueous acidic conditions. In order to be
sure that the pinacol acetal was readily hydrolysed in the presence
of other acid sensitive groups 44 was deemed a good substrate.
Dissolving 44 in a 1:1 mixture of tetrahydrofuran and 1 M aqueous
hydrochloric acid the reaction was monitored (TLC) every 2 h; after
6 h no change was observed. Increasing the temperature to 50 ꢀC
OBn
OBn
O
O
CO2tBu
tBuO2C
O
O
N
OtBu
OHC
CHO
N
tBuO
CO2CH3
CO2CH3
39
40
+
1. 2-tert-butoxyaniline
4Å molecular sevies, rt
OBn
O
O
CO2tBu
OtBu
2. tert-butyl diazoacetate
pyridinium triflate
OHC
N
CH2Cl2, -30 °C
82% yield
40 : 41 = 2.56 : 1
CO2CH3
41
OBn
OBn
pinacol
pTSA (cat)
O
O
O
O
toluene
reflux, 6 hrs
86% yield
Scheme 10. One-pot, two-step synthesis of bis-cis-aziridine derived triaryl biether 40
and mono-cis-aziridine derived triaryl biether 41 from 39.
O
O
OHC
CHO
O
42
CO CH
O
39
CO CH
1. LiAlH
THF
-15 - 0 °C, 3 hrs
X-ray crystal
structure
yield.
97% yield
Confident the mono-aza-Darzens cis-aziridination was robust,
we wanted to evaluate, for the first time, if a racemic double-aza-
Darzens was viable using 2-tert-butoxyaniline, tert-butyl diazo-
acetate, O-benzyl bis-aldehyde 39, pyridinium triflate (10 mol%)
and the conditions outlined in Scheme 10. Gratifyingly, after work-
up, 1H NMR indicated the impure reaction mixture contained two
cis-aziridines and a small amount of a tentatively assigned trans-
aziridine (J 2.4 Hz, not isolated and not shown). Further analysis (1H
NMR) revealed the cis:trans diastereoselectivity to be > 99:1. Sub-
sequent purification via flash chromatography afforded a combined
82% yield of cis-40 and cis-41 (both C2,3 aziridines had J 6.7 Hz).
Physicochemical analysis established the major product was double
cis-aziridine 40 (59% yield, Scheme 10) whilst the minor was mono-
cis-aziridine 41 (23% yield). We propose that bis-cis-aziridine 40
originates, presumably, from mono-cis-aziridine 41. But, generating
40 with two cis-aziridines raised the question of their relative
stereochemistry; that is, does it have meso- or C2-symmetry?
2. MnO
CH Cl
rt, 18 hrs
69% yield
39
OBn
OBn
O
O
NaH
MTP-Br
THF
O
O
O
O
O
O
O
0 °C, 4 hrs
76% yield
O
O
O
44
43
O
X-ray crystal
structure
43
Scheme 11. Transforming ester 42 into styrene 44 and the X-ray crystal structure of
mono-aldehyde 43.

6
S.P. Bew et al. / Tetrahedron 75 (2019) 130532
T/ꢀC
D
and are reported as follows: [
a
]
concentration (c ¼ g/100 mL,
solvent). MALDI-TOF mass spectra were recorded on a Shimadzu
Axima-CFR spectrometer. High resolution mass spectrometry
(HRMS) was carried out by the EPSRC National Mass Spectrometry
Facility (Swansea, UK). Melting points of crystalline solids were
recorded using a Stuart Scientific SMP1 apparatus (solvent of
crystallization in brackets) and are uncorrected. Percentage yield
refers to the isolated yield of analytically pure material unless
otherwise stated. Dichloromethane was distilled from calcium hy-
dride before use. Chloroform and d-chloroform were filtered
through basic alumina and stored over 4 Å molecular sieves.
Tetrahydrofuran was distilled from sodium/benzophenone prior to
use. All other solvents and reagents were purchased from com-
mercial sources (Sigma-Aldrich, Alfa Aesar, Fluorochem and Fisher
Scientific) and used as received.
Scheme 12. Synthesis of rac-mono-cis-aziridine derived alkene 46 from dialdehyde
45.
and stirring for a further 3 h 44 was completely consumed. Sub-
sequent flash column chromatography afforded 45 (Scheme 12) in a
90% yield. No alkene polymerization or aldehyde hydration was
observed. Finally, mono-aziridination of 45 was accomplished us-
ing pyridinium triflate (10 mol%) and 2-tert-butoxyaniline (0.98
eqn), the desired mono-cis-aziridine 46 (J C2,3 6.7 Hz) was afforded
in a 65% yield, which based on recovered 46, increased to 87% yield.
4.1.1. Methyl 3,5-bis(4-formylphenoxy)-4-hydroxybenzoate (22)
4.1.1.1. Synthesis A: microwave irradiation. To a 15 mL microwave
vial under a nitrogen atmosphere was added methyl 3,4,5-
trihydroxybenzoate 20 (500 mg, 2.72 mmol, 1 equiv.), cesium car-
bonate (2.41 g, 7.40 mmol, 2.7 equiv.) and a magnetic stirrer bar.
Dimethyl sulfoxide (7 mL) was added, and the resulting mixture
stirred vigorously for 10 min at room temperature before the
addition of 4-fluorobenzaldehyde 21 (0.93 mL, 8.69 mmol, 3.2
equiv.) via a 2.5 mL syringe. The vial was sealed with a PTFE-lined
aluminium crimp cap and the dark red suspension heated at
160 ꢀC in a Biotage microwave reactor for 3 h, after which the re-
action mixture was allowed to cool to room temperature and
poured into a 250 mL separating funnel containing 1 M aqueous
hydrochloric acid (50 mL). The aqueous mixture was extracted with
ethyl acetate (2 ꢁ 50 mL) and the combined organic extracts were
washed with distilled water (3 ꢁ 50 mL) and then brine (50 mL).
The solution was dried over magnesium sulfate, filtered, and the
solvent removed in vacuo to afford a dark brown residue. Purifi-
cation via flash column chromatography on silica gel (eluent:
dichloromethane/ethyl acetate 9:1; Rf ¼ 0.30) afforded a pale-
yellow solid (600 mg, 1.53 mmol, 56% yield) whose physicochem-
ical characteristics were consistent with those of title compound
22.
4. Conclusion
In summary, we have demonstrated the facile application of
single or double early stage SNAr and aza-Darzens chemistry for the
straightforward production of functionalised cis-aziridine-derived
biaryl ethers and triaryl biethers e potential precursors to a- or b-
amino acid derived backbone C-O-D-O-E scaffolds found in glyco-
peptide natural products. Using either conventional flask or flow-
chemistry protocols the first example of a double SNAr on a single
substrate has been shown to be viable on a multigram scale.
Furthermore, we have demonstrated the feasibility of incorporating
aryl ether bond formation early on in the synthesis of the C-O-D-O-
E component, and as natural product precursors and sought-after
motifs, they can be adorned with readily manipulated functional
groups, e.g. phenol, ester and aldehyde, without invoking a pro-
tecting/deprotecting group strategy. Finally, we show how a double
aldehyde derived starting material can be transformed via an
organoBrønsted acid catalysed aza-Darzens reaction into a mono-
or bis-cis-aziridine-derived triaryl biether adorned with ester,
aldehyde, alkene and O-benzyl ether functional groups.
M.p. 161e162 ꢀC; 1H NMR (300 MHz, CDCl3)
d
¼ 9.95 (s, 2H,
-CHO), 7.92 (d, J 8.8 Hz, 4H, Ar-H), 7.65 (s, 2H, Ar-H), 7.17 (d, 4H, J
8.8 Hz, Ar-H), 6.50 (s, 1H, -OH), 3.84 (s, 3H, -CO2CH3); 13C NMR
(75 MHz, CDCl3)
d
¼ 190.9 (-CHO), 165.3 (-CO2CH3), 161.7, 144.6,
4.1. Experimental section
143.0, 133.0, 132.2, 122.8, 119.0, 117.4, 52. (-CO2CH3); FT-IR (ATR):
y
(cmꢂ1) ¼ 3079 (OeH), 2846 (CeH), 1692 (ester C]O), 1669 (alde-
hyde C]O), 1578, 1502, 1423, 1341, 1194; MS (MALDI-TOF): m/z
414.82 [MþNa]þ; HRMS (APCI) exact mass calculated for C22H17O7
requires m/z 393.0969, found m/z 393.0965 [MþH]þ.
Air and water-sensitive reactions were carried out under a ni-
trogen atmosphere and anhydrous conditions with magnetic stir-
ring unless otherwise stated. Analytical thin-layer chromatography
(TLC) was performed on Merck silica gel 60 F254 plates (0.2 mm),
with visualization by UV light and/or potassium permanganate
stain followed by heating. Flash column chromatography was per-
4.1.2. Methyl 3-(4-formylphenoxy)-4,5-dihydroxybenzoate (23)
A by-product was isolated during the column chromatography
(Rf ¼ 0.60; dichloromethane/methanol 2%); this was identified as
methyl 3-(4-formylphenoxy)-4,5-dihydroxybenzoate 23 (165 mg,
0.57 mmol, 21% yield).
formed using Davisil silica gel 60 (40e63 m
m). 1H and 13C NMR
spectra were recorded on a Bruker Avance spectrometer 500
(500 MHz), an Oxford Gemini 400 spectrometer (400 MHz) or an
Oxford Gemini 300 spectrometer (300 MHz). Chemical shifts are
reported in
d
(ppm) and referenced to residual solvent signals (1H
M.p. 191e193 ꢀC (chloroform); 1H NMR (300 MHz, CD3OD)
NMR: CDCl3 at 7.26 ppm, CD3CN at 1.94 ppm; 13C NMR: CDCl3 at
77.16 ppm, CD3CN at 1.32, 118.26 ppm). Signal multiplicities are
described as follows: s ¼ singlet, d ¼ doublet, dd ¼ doublet of
doublets, t ¼ triplet, q ¼ quartet, m ¼ multiplet, br ¼ broad. FT-IR
spectra were recorded on a Perkin Elmer Spectrum 100 spec-
trometer as thin films on sodium chloride plates and are reported in
wavenumbers (cmꢂ1). Optical rotations were measured using a
Perkin Elmer 241 polarimeter with a 1 mL cell (path length 1 dm)
d
9.77 (s, 1H, -CHO), 7.86 (d, J 9.0 Hz, 2H, Ar-H), 7.36 (s, 1H, Ar-H),
7.19 (s, 1H, Ar-H), 7.02 (d, J 9.0 Hz, 2H, Ar-H), 3.79 (s, 3H, -CO2CH3);
13C NMR (75 MHz, CD3OD)
¼ 191.3,166.6,163.3,146.8,142.9,141.8,
d
133.6, 131.3, 120.8, 116.2, 114.6, 113.2, 51.1; FT-IR (thin film):
y
(cmꢂ1) ¼ 3217 (OeH), 1686 (C]O), 1593, 1504, 1439, 1319, 1224,
1156; MS (MALDI-TOF) m/z 311.12 [MþNa]þ; HRMS (NESI) exact
mass calculated for C15H11O6 requires m/z 287.0561, found m/z
287.0566 [M ꢂ H]-.

S.P. Bew et al. / Tetrahedron 75 (2019) 130532
7
4.1.3. Methyl 3,5-bis(4-formylphenoxy)-4-hydroxybenzoate (22)
4.1.3.1. Synthesis B: conventional heating. To a 500 mL two-necked
round-bottom flask was added methyl 3,4,5-trihydroxybenzoate 20
(9.93 g, 53.9 mmol, 1 equiv.) and a magnetic stirrer bar. The white
solid was dissolved in dimethyl sulfoxide (160 mL) under a nitrogen
atmosphere. Cesium carbonate (52.7 g, 162 mmol, 3 equiv.) was
added in one portion and the resulting mixture stirred at room
temperature for 15 min before the addition of 4-
chromatography on silica gel (eluent: dichloromethane/ethyl ace-
tate 9:1) afforded a yellow solid (603 mg, 2.09 mmol, 39% yield)
whose physicochemical properties matched those of the title
compound (22). By-product 23 was isolated in a 7% yield (149 mg,
0.38 mmol); the physicochemical properties were as outlined
previously.
fluorobenzaldehyde 21 (14.4 mL, 135 mmol, 2.5 equiv.) via
a
4.1.6. Methyl 7-hydroxy-2-(4-methoxyphenyl)benzo[d][1,3]dioxole-
5-carboxylate (25)[17]
25 mL syringe. The flask was fitted with a reflux condenser and the
reaction mixture heated at 120 ꢀC for 48 h using an aluminium
heating block mounted on a hotplate magnetic stirrer. When no
further conversion from 20 to 22 was observed by thin layer
chromatography (eluent: dichloromethane/ethyl acetate 9:1), the
reaction mixture was cooled to 0 ꢀC, quenched with 1 M aqueous
hydrochloric acid (200 mL) and poured into a 2 L separating funnel.
The aqueous mixture was extracted with ethyl acetate (2 ꢁ 200 mL)
and the combined organic extracts were washed with distilled
water (3 ꢁ 300 mL) and then brine (250 mL). The solution was dried
over magnesium sulfate, filtered, and the solvent removed in vacuo
to afford a dark brown solid. Trituration with diethyl ether (0 ꢀC)
afforded a cream solid (8.89 g, 22.7 mmol, 42% yield) whose phys-
icochemical properties were consistent with those of the title
compound (22) described previously.
A flame-dried 250 mL two-necked round-bottom flask fitted
with a Soxhlet apparatus containing 4 Å molecular sieves was
charged with a solution of p-anisaldehyde dimethyl acetal 24
(2.18 g, 12.0 mmol, 1.25 equiv.) in anhydrous toluene (100 mL) and a
magnetic stirrer bar. Methyl gallate 20 (1.77 g, 9.60 mmol, 1 equiv.)
and para-toluenesulfonic acid (8 mg, 0.046 mmol, 0.5 mol%) were
added, and the solution heated at reflux for 3 h. After cooling to
room temperature, the majority of the solvent was removed in
vacuo. The residue was redissolved in dichloromethane (50 mL) and
washed with saturated aqueous sodium carbonate solution
(50 mL). The addition of hexane (50 mL) resulted in the precipita-
tion of a pale-yellow solid, which was filtered and recrystallised
from dichloromethane/hexane (1:1) to afford a cream solid whose
physicochemical properties matched those previously reported for
25 (1.20 g, 3.97 mmol, 41% yield).
4.1.4. Methyl 3,5-bis(4-formylphenoxy)-4-hydroxybenzoate (22)
4.1.4.1. Synthesis C: flow reactor. A Uniqsis Flow Syn reactor was
fitted with a 6.6 ꢁ 100 mm glass column packed with cesium car-
bonate (5 g). The column was pre-heated to 150 ꢀC. A solution of
methyl 3,4,5-trihydroxybenzoate 20 (200 mg, 1.09 mmol, 1 equiv.)
in dimethyl sulfoxide (2 mL), solution A, and a solution of 4-
fluorobenzaldehyde 26 (0.4 mL, 2.78 mmol, 2.5 equiv.) in
dimethyl sulfoxide (2 mL), solution B, were pumped simulta-
neously through the glass column, each with a flow rate of 1 mL/
min. The dark red solution was collected in a 250 mL separating
funnel containing 1 M hydrochloric acid (50 mL) at room temper-
ature. The aqueous mixture was extracted with ethyl acetate
(3 ꢁ 30 mL) and the combined organic layers were washed with
distilled water (3 ꢁ 50 mL) and then brine (50 mL). The organic
solution was dried over magnesium sulfate, filtered, and the solvent
removed in vacuo. Purification via flash column chromatography on
silica gel (eluent: dichloromethane/ethyl acetate 9:1) afforded 22 as
a pale-yellow solid (141 mg, 0.36 mmol, 33% yield) and 23 as a light
brown solid (91 mg, 0.32 mmol, 29% yield). The physicochemical
properties of these compounds matched the data obtained from the
microwave-promoted synthesis outlined above.
M.p.130e132 ꢀC (dichloromethane/hexane); 1H NMR (500 MHz,
CDCl3)
d 7.44 (d, J 8.8 Hz, 2H, Ar-H), 7.27 (d, J 1.5 Hz, 1H, Ar-H), 7.11
(d, J 1.5 Hz, 1H, Ar-H), 6.93 (s, 1H, -CH-), 6.89 (d, J 8.8 Hz, 2H, Ar-H),
5.00 (s, 1H, -OH), 3.81 (s, 3H, -OCH3), 3.77 (s, 3H, -OCH3); FT-IR (thin
film):
y
(cmꢂ1) ¼ 3347 (OeH), 2920 (CeH), 2850 (CeH), 1696 (C]
O), 1637, 1617, 1516, 1449, 1375, 1257, 1081; MS (MALDI-TOF) m/z
325.08 [MþNa]þ.
4.1.7. Methyl 7-(4-formylphenoxy)-2-(4-methoxyphenyl)benzo[d]
[1,3]dioxole-5-carboxylate (26)
A 15 mL microwave vial containing 4 Å molecular sieves was
flame-dried and allowed to cool to room temperature under a flow
of nitrogen. Methyl 3-(4-formylphenoxy)-4,5-dihydroxybenzoate
23 (100 mg, 0.347 mmol, 1 equiv.), anhydrous toluene (7 mL),
para-anisaldehyde dimethyl acetal 24 (66 mg, 0.364 mmol, 1.05
equiv.), and para-toluenesulfonic acid (0.35 mg, 0.0018 mmol,
0.5 mol%) were added. The vial was sealed with a PTFE-lined
aluminium crimp cap and the stirred suspension was heated at
110 ꢀC for 6 h. After cooling to room temperature, sodium carbonate
(0.4 mg, 0.0038 mmol, 1.09 mol%) was added and the mixture stir-
red at room temperature for 1 h before being filtered to remove the
molecular sieves. The solvent was removed in vacuo, and purifica-
tion via flash column chromatography on silica gel (eluent:
dichloromethane 100%; Rf ¼ 0.30) afforded a pale-yellow solid
whose physicochemical properties were consistent with those of
the title compound 26 (20 mg, 0.049 mmol, 28% yield).
4.1.5. Methyl 3-(4-formylphenoxy)-4,5-dihydroxybenzoate (22)
To
a 15 mL microwave vial was added methyl 3,4,5-
trihydroxybenzoate 20 (1 g, 5.43 mmol, 1 equiv.), cesium carbon-
ate (3.89 g,11.9 mmol, 2.2 equiv.) and a magnetic stirrer bar. The vial
was purged with nitrogen, sealed with a PTFE-lined aluminium
crimp cap and dimethyl sulfoxide (10 mL) was added via a 20 mL
syringe. The resulting reaction mixture was stirred vigorously for
10 min at room temperature before the addition of 4-
fluorobenzaldehyde 21 (0.7 mL, 6.53 mmol, 1.2 equiv.) via a 2 mL
syringe. The dark red suspension was heated to 120 ꢀC in a Biotage
microwave reactor for 90 min. The reaction mixture was allowed to
cool to room temperature and poured into a 250 mL separating
funnel containing 1 M aqueous hydrochloric acid (50 mL). The
aqueous mixture was extracted with ethyl acetate (2 ꢁ 50 mL) and
the combined organic extracts were washed with distilled water
(2 ꢁ 100 mL) and then brine (100 mL). The resulting solution was
dried over magnesium sulfate, filtered, and the solvent removed in
vacuo to afford a dark brown residue. Purification via flash column
M.p. 76e78 ꢀC; 1H NMR (400 MHz, CDCl3)
d 9.93 (s, 1H, -CHO),
7.82 (d, J 8.7 Hz, 2H, Ar-H), 7.46e7.39 (m, 4H, Ar-H), 7.07e7.02 (m,
3H, Ar-H), 6.90 (d, J ¼ 8.7 Hz, 2H, Ar-H), 3.85 (s, 3H, -CO2CH3), 3.80
(s, 3H, -OCH3); 13C NMR (126 MHz, CDCl3)
d 190.8 (-CHO), 165.8
(-CO2CH3), 161.8, 161.5, 150.0, 142.7, 136.4, 132.0, 131.7, 128.0, 126.9,
124.9, 118.3,116.9,114.1,112.65,106.8, 55.4 (-OCH3), 52.4 (-CO2CH3);
FT-IR (thin film):
y
(cmꢂ1) ¼ 3076 (CeH), 3011 (CeH), 2949 (CeH),
2843 (CeH), 2733 (CeH), 1717 (ester C]O), 1696 (aldehyde C]O),
1614,1600,1518,1500,1442,1367, 1301, 1253,1222,1178,1157,1020,
1006; MS (MALDI-TOF) m/z 405.25 [M ꢂ H]-; HRMS (HNESP) exact
mass calculated for C23H19O7 requires m/z 407.1125, found m/z
407.1128 [MþH]þ.

8
S.P. Bew et al. / Tetrahedron 75 (2019) 130532
4.1.8. Methyl 3,4-bis(benzyloxy)-5-(4-formylphenoxy)benzoate
(28)
4.1.10. Methyl 3-((tert-butyldiphenylsilyl)oxy)-5-(4-
formylphenoxy)-4-methoxybenzoate (30)
To a 250 mL round-bottom flask containing methyl 3-(4-
formylphenoxy)-4,5-dihydroxybenzoate 23 (333 mg, 1.16 mmol, 1
To
a
5 mL round-bottom flask containing methyl 3-(4-
29 (100 mg,
formylphenoxy)-5-hydroxy-4-methoxybenzoate
equiv.) under
a
nitrogen atmosphere was added N,N-dime-
0.33 mmol, 1 equiv.) and a magnetic stirrer bar under a nitrogen
atmosphere was added N,N-dimethylformamide (2 mL). To the
stirred orange solution was added imidazole (50 mg, 0.73 mmol, 2.2
equiv.) in one portion, followed by the addition of tert-butyldi-
thylformamide (35 mL) and a magnetic stirrer bar. Potassium car-
bonate (481 mg, 3.48 mmol, 3 equiv.) was added to the stirred
orange solution in one portion, following by the addition of benzyl
bromide (0.41 mL, 3.48 mmol, 3 equiv.) via a 1 mL syringe. The
resulting suspension was heated to 120 ꢀC for 7 h. After cooling to
room temperature, distilled water (30 mL) was added, followed by
1 M aqueous hydrochloric acid (40 mL). The mixture was extracted
with ethyl acetate (2 ꢁ 50 mL) and the combined organic layers
were washed with distilled water (2 ꢁ 100 mL) and then brine
(100 mL) before being dried over magnesium sulfate, filtered, and
the solvent removed in vacuo. Purification via flash column chro-
matography on silica gel (eluent: petroleum ether/diethyl ether
7:3; Rf ¼ 0.20) afforded a cream solid whose physicochemical
properties were consistent with those of the title compound 28
(398 mg, 0.85 mmol, 73% yield).
phenylchlorosilane (95 mL, 0.36 mmol, 1.1 equiv.) via a 250 mL sy-
ringe. The pale-yellow solution was stirred at room temperature for
18 h before being poured into a 50 mL separating funnel containing
5% aqueous sodium bicarbonate solution (10 mL) and the organics
extracted with hexane (3 ꢁ 10 mL). The combined organic layers
were washed with brine (30 mL), dried over magnesium sulfate,
filtered, and the solvent removed in vacuo. Purification via flash
column chromatography on silica gel (eluent: petroleum ether/
diethyl ether 1:1; Rf ¼ 0.56) afforded a colourless oil whose physi-
cochemical properties were consistent with those of the title
compound 30 (102 mg, 0.19 mmol, 57% yield).
1H NMR (500 MHz, CDCl3)
d 9.91 (s, 1H, -CHO), 7.72e7.64 (m 6H,
M.p. 88e90 ꢀC (hexane/dichloromethane); 1H NMR (400 MHz,
CDCl3) d 9.84 (s,1H, -CHO), 7.74 (d, J 8.6 Hz, 2H, Ar-H), 7.55 (s,1H, Ar-
Ar-H), 7.39e7.18 (m, 8H, Ar-H), 6.75 (d, J 8.6 Hz, 2H, Ar-H), 3.66 (s,
3H, -CO2CH3), 3.56 (s, 3H, -OCH3), 1.06 (s, 9H, -C(CH3)3); 13C NMR
H), 7.40e7.29 (m, 6H, Ar-H), 7.19e7.08 (m, 5H, Ar-H), 6.96 (d, J
8.6 Hz, 2H, Ar-H), 5.12 (s, 2H, -CH2Ph), 5.00 (s, 2H, -CH2Ph), 3.81 (s,
(126 MHz, CDCl3) d 190.8, 165.7, 162.9, 149.8, 147.6, 147.2, 135.5,
132.3, 132.0, 131.2, 130.1, 127.8, 125.4, 119.5, 117.2, 116.4, 60.8, 52.2,
3H, -CO2CH3); 13C NMR (126 MHz, CDCl3)
d
190.7,166.0,162.9,153.2,
147.7, 144.7, 136.6, 136.0, 131.9, 131.3, 128.7, 128.3, 128.2, 128.15,
127.7, 125.9, 116.7, 116.7, 112.1, 75.2, 71.4, 52.4; FT-IR (thin film):
26.6, 19.7; FT-IR (thin film):
y
(cmꢂ1) ¼ 3074 (CeH), 2956 (CeH),
2859 (CeH), 1726 (C]O), 1700 (C]O), 1603, 1582, 1506, 1430, 1345,
1227, 1155, 1109, 1071, 999; MS (MALDI-TOF) m/z 579.28 [MþK]þ;
HRMS (NESI) exact mass calculated for C32H33O6Si requires m/z
541.2041, found m/z 541.2038 [MþH]þ.
y
(cmꢂ1) ¼ 3064 (OeH), 3033, 2952, 2736 (CeH), 1724 (C]O), 1697,
1584, 1503, 1427, 1341, 1220, 1157, 1076; MS (MALDI-TOF) m/z
491.05 [MþNa]þ, 507.00 [MþK]þ; HRMS (HNESP) exact mass
calculated for C29H25O6 requires m/z 469.1646, found m/z 469.1642
[MþH]þ.
4.1.11. Methyl 3,5-bis(4-formylphenoxy)-4-methoxybenzoate (31)
To
a 15 mL microwave vial was added methyl 3,5-bis(4-
formylphenoxy)-4-hydroxybenzoate 22 (500 mg, 1.27 mmol, 1
equiv.), potassium carbonate (352 mg, 2.55 mmol, 2 equiv.) and a
magnetic stirrer bar. N,N0-Dimethylformamide (6 mL) was added
and the vial sealed with a PTFE-lined aluminium crimp cap. The
suspension was stirred at room temperature for 15 min. Iodo-
4.1.9. Methyl 3-(4-formylphenoxy)-5-hydroxy-4-methoxybenzoate
(29)
To
a
15 mL microwave vial containing methyl 3-(4-
formylphenoxy)-4,5-dihydroxybenzoate 23 (603 mg, 2.09 mmol, 1
equiv.) and a magnetic stirrer bar under a nitrogen atmosphere was
added N,N-dimethylformamide (10 mL). To the stirred orange so-
lution was added lithium carbonate (155 mg, 2.09 mmol, 1 equiv.)
in one portion, followed by the addition of iodomethane (0.13 mL,
2.09 mmol, 1 equiv.) dropwise via a 1 mL syringe. The vial was
sealed with a PTFE-lined aluminium crimp cap and heated to 55 ꢀC
for 18 h using a sand bath. After cooling to room temperature, the
mixture was poured into a 250 mL separating funnel containing
distilled water (20 mL), to which 1 M aqueous hydrochloric acid
(50 mL) was added. The mixture was extracted with ethyl acetate
(3 ꢁ 50 mL) and the combined organic layers were washed with
distilled water (3 ꢁ 100 mL) and subsequently brine (100 mL). The
organic solution was dried over magnesium sulfate, filtered, and
the solvent removed in vacuo. Purification via flash column chro-
matography on silica gel (eluent: dichloromethane/diethyl ether
5%; Rf ¼ 0.31) afforded an orange oil whose physicochemical
properties were consistent with those of the title compound 29
(449 mg, 1.49 mmol, 71% yield).
methane (111 mL, 1.78 mmol, 1.4 equiv.) was added via a 250 mL
syringe, and the mixture heated at 80 ꢀC for 24 h. After cooling to
room temperature, the suspension was poured into a 250 mL
separating funnel containing ethyl acetate (50 mL) and 1 M
aqueous hydrochloric acid (50 mL). The aqueous layer was re-
extracted with ethyl acetate (50 mL) and the combined organic
layers were washed with distilled water (2 ꢁ 100 mL) and subse-
quently brine (100 mL) before being dried over magnesium sulfate
and filtered. The solvent was removed in vacuo to afford a yellow oil
whose physicochemical characteristics were consistent with those
of the title compound (31, 478 mg, 1.18 mmol, 92%) was used as is.
1H NMR (500 MHz, CDCl3)
d 9.88 (s, 2H, -CHO), 7.81 (d, J 8.7 Hz,
4H, Ar-H), 7.62 (s, 2H, Ar-H), 7.01 (d, J 8.7 Hz, 4H, Ar-H), 3.81 (s, 3H,
-OCH3), 3.72 (s, 3H, -OCH3); 13C NMR (126 MHz, CDCl3) 190.6, 165.1,
162.4, 148.7, 148.1, 132.1, 131.8, 126.1, 120.7, 117.0, 61.3 (-OCH3), 52.5;
FT-IR (thin film):
y
(cmꢂ1) ¼ 2955 (CeH), 2836 (CeH), 2738 (CeH),
1727 (ester C]O), 1697 (aldehyde C]O), 1602, 1579, 1503, 1421,
1335, 1223, 1156; MS (MALDI-TOF) m/z 429.2 [MþNa]þ, 445.21
[MþK]þ; HRMS (NESP) exact mass calculated for C23H19O7 requires
m/z 407.1125, found m/z 407.1125 [MþH]þ.
1H NMR (500 MHz, CDCl3)
d 9.86 (s, 1H, -CHO), 7.81 (d, J 8.8 Hz,
2H, Ar-H), 7.47 (d, 1H, Ar-H), 7.25 (d, 1H, Ar-H), 6.99 (d, J 8.8 Hz, 2H,
Ar-H), 5.95 (s, 1H), 5.23 (s, 1H, -OH), 3.88 (s, 3H, -OCH3), 3.80 (s, 3H,
-OCH3); 13C NMR (126 MHz, CDCl3)
d
190.6, 166.1, 162.4, 148.6,
4.1.12. tert-Butyl 3-(4-(2,3-bis(benzyloxy)-5-(methoxycarbonyl)
phenoxy)phenyl)-1-(2-(tert-butoxy)phenyl)-cis-aziridine-2-
carboxylate (32)
To a flame-dried 5 mL microwave vial containing crushed 4 Å
molecular sieves under a nitrogen atmosphere was added a solu-
tion of methyl 3,4-bis(benzyloxy)-5-(4-formylphenoxy)benzoate
147.95, 132.1, 131.8, 126.1, 120.7, 116.8, 61.3, 52.5; FT-IR (thin film):
y
(cmꢂ1) ¼ 3384 (OeH), 2955, 2843 (CeH), 1709 (C]O), 1582, 1503,
1436, 1354, 1227, 1156; MS (MALDI-TOF) m/z 325.03 [MþNa]þ;
HRMS (NESI) exact mass calculated for C16H15O6 [MþH]þ requires
m/z 303.0863, found m/z 303.0866.

S.P. Bew et al. / Tetrahedron 75 (2019) 130532
9
28 (100 mg, 0.21 mmol, 1 equiv.) and 2-tert-butoxyaniline (33 mg,
0.20 mmol, 0.95 equiv.) in anhydrous dichloromethane (2 mL). The
mixture was stirred slowly at room temperature for 18 h. After the
addition of pyridinium triflate (5 mg, 0.02 mmol, 10 mol%), the vial
was sealed with a PTFE-lined aluminium crimp cap and cooled to
Diluting the reaction with ethyl acetate (100 mL), the solution was
transferred to a 250 mL separating funnel, washed with saturated
brine (100 mL), dried with magnesium sulfate, filtered and the
solvent removed under reduced pressure. After solvent removal the
largely pure material was passed through a plug of silica gel and
eluted quickly with 20% diethyl ether in 40e60 petroleum ether.
The pale-yellow oil (95% yield) was carried on to the synthesis of 35.
0 ꢀC. Tert-butyl diazoacetate (30
dropwise via a 100
L syringe. The solution was stirred at 0 ꢀC for
mL, 0.21 mmol, 1 equiv.) was added
m
18 h before being filtered through a short plug of silica and eluted
with diethyl ether (3 ꢁ 5 mL). The organic solvent was removed in
vacuo to afford a dark yellow residue. Purification via flash column
chromatography on silica gel (eluent: petroleum ether/diethyl
ether/dichloromethane 8:1:1; Rf ¼ 0.20), afforded a white solid
whose physicochemical properties were consistent with those of
the title compound 32 (89 mg, 0.12 mmol, 64% yield).
4.1.15. Benzyl (R)-2-hydroxy-1-(3-(3-(4,4,5,5-tetramethyl-1,3-
dioxolan-2-yl)phenoxy)phenyl)ethylcarbamate (36)
To a 25 mL round bottom flask, equipped with a magnetic stirrer
bar, under nitrogen was added benzyl carbamate (489 mg,
3.24 mmol) and sodium hydroxide (129 mg, 3.24 mmol). 1-
Propanol (4 mL) water (5 mL) was added via syringe and the
mixture cooled to 0 ꢀC. Tert-butyl hypochlorite (0.37 mL,
3.24 mmol) was added and the mixture stirred at 0 ꢀC for 10 min. A
solution of (DHQD)2PHAL (50.4 mg, 0.06 mmol) in 1-propanol
(4 mL) was added, followed by 4,4,5,5-tetramethyl-2-(3-)3-
vinylphenoxy)phenyl)-1,3-dioxolane 35 (350 mg, 1.08 mmol) in 1-
propanol (4 mL). Adding potassium osmate dihydrate (15.9 mg,
0.04 mmol) the reaction was stirred for 3 h changing from deep
green to yellow. Quenching it with saturated aqueous sodium sul-
fite (30 mL), it was diluted with ethyl acetate (50 mL) and trans-
ferred to a 250 mL separating funnel. The organic layer was
separated, washed with saturated brine (40 mL), dried with mag-
nesium sulfate, filtered and the solvent removed in vacuo. The
product was purified via flash chromatography on silica agel (30%
ethyl acetate in 40e60 petroleum ether) affording an oil in a 65%
yield. A sample was submitted to chiral HPLC analysis [cellulose 1
iso-hexane/iso-propanol: 85/15 1 mL/min, 8.85 min (1st peak),
17.31 min (2nd peak, 96% e.e.)]
M.p. 39e41 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.48e7.15 (m, 14H,
Ar-H), 6.94e6.82 (m, 6H, Ar-H), 5.10 (s, 2H, -CH2Ph), 5.06 (s, 2H,
-CH2Ph), 3.76 (s, 3H, -OCH3), 3.38 (d, J 6.7 Hz, 1H, aziridine CeH),
2.96 (d, J 6.7 Hz, 1H, aziridine CeH), 1.31 (s, 9H, -C(CH3)3), 1.16 (s, 9H,
-C(CH3)3); 13C NMR (126 MHz, CDCl3)
d 167.1, 166.2, 156.6, 153.0,
150.1, 148.0, 146.55, 144.1, 137.1, 136.4, 130.2, 129.45, 128.6, 128.5,
128.2, 128.15, 128.0, 127.7, 125.4, 123.14, 123.11, 123.0, 120.1, 117.4,
114.8, 110.6, 81.3, 80.3, 75.2, 71.3, 53.4, 52.2, 47.4, 47.0, 28.7, 27.9; FT-
IR (thin film):
1490, 1424, 1367, 1338, 1210, 1164, 1077; HRMS (NESI) exact mass
y
(cmꢂ1) 3070, 3035, 2976, 2880, 1716 (C]O), 1585,
calculated for
C45H48O8N requires m/z 730.3374, found m/z
730.3376 [MþH]þ.
4.1.13. 3-(3-(4,4,5,5-Tetramethyl-1,3-dioxolan-2-yl)phenoxy)
benzaldehyde (34)
A
20 mL microwave vial was charged with 3-(4,4,5,5-
tetramethyl-1,3-dioxolan-2-yl)phenol 33 (1 g, 4.5 mmol), 3-
bromobenzaldehyde (0.5 mL, 4.5 mmol), potassium carbonate
(0.9 g, 6.75 mmol), 1,10-phenanthroline (162 mg, 0.90 mmol) and
copper(I) iodide (86.0 mg, 0.45 mmol). Anhydrous pyridine (15 mL)
was added via syringe. The vial was heated at 190 ꢀC under mi-
crowave irradiation for 5 h after which it was allowed to cool to
room temperature and diluted by addition of DCM (100 mL) in a
250 mL separating funnel. The solution was washed with aqueous
saturated copper sulfate (100 mL), aqueous 1 M hydrochloric acid
(100 mL), saturated brine (40 mL), and dried with magnesium sul-
fate. Filtering off the drying agent and removing the solvent affor-
ded an oil that was purified via flash chromatography on silica gel
(5% ethyl acetate in 40e60 petroleum ether. The product, a pale-
yellow oil (67% yield), was analysed and confirmed to be the title
compound (34).
1H NMR (500 MHz, CDCl3)
d 7.13e6.87 (m,11H, Ar-H), 6.69 (s,1H,
Ar-H), 5.88 (s, 1H, Ar-H), 5.12 (s, 1H), 5.00 (s, 1H), 4.91 (s, 1H), 4.60 (s,
1H), 3.45 (m, 1H), 3.15 (m, 1H), 1.25 (s, 6H, 2 x CH3), 1.21 (s, 6H, 2 x
CH3); 13C NMR (126 MHz, CDCl3)
d
157.7, 157.2, 150.5, 141.5, 137.9,
136.9, 136.3, 134.4, 128.6, 128.5, 128.2, 128.17, 128.15, 128.0, 127.9,
117.5,113.8, 99.6, 82.7, 75.3 72.9, 67.0, 48.4, 24.5, 22.25; [
25 -15.1 (c
a
]
D
1.0 CHCl3); FT-IR (thin film):
y
(cmꢂ1) 3406, 3333, 2977, 1704 (C]
O), 1584, MS (MALDI) 514.4 [M þ Na]þ; HRMS (HNESP) exact mass
calculated for C29H33NO6NH4 requires m/z 509.2646, found m/z
509.2655 [M þ NH4]þ.
4.1.16. Methyl (R)-2-(benzyloxycarbonylamino)-2-(3-(3-(4,4,5,5-
tetramethyl-1,3-dioxolan-2-yl)phenoxy)phenyl)acetate (38)
To a 25 mL round bottom flask, equipped with a magnetic stirrer
bar, under nitrogen was added benzyl (R)-2-hydroxy-1-(3-(3-
(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenoxy)phenyl)ethyl-
carbamate 36 (0.3 g, 0.61 mmol). Acetone (10 mL) and aqueous
sodium bicarbonate solution (5 mL) were added and the mixture
cooled to 0 ꢀC. To this was added sequentially sodium bromide
(8 mg, 0.07 mmol) and TEMPO (105 mg, 0.67 mmol). Sodium hy-
pochlorite (11% chlorine) (1.03 mL, 1.83 mmol) was added dropwise
via syringe over a period of 10 min, while the mixture was vigor-
ously stirred and maintained at 0 ꢀC. After 3 h, acetone was
removed under reduced pressure, the residue diluted with water
(10 mL), transferred into a 50 mL separating funnel and washed
with ether (2 ꢁ 20 mL). The aqueous phase was acidified to pH 4
and extracted with ethyl acetate (2 ꢁ 20 mL). The combined organic
layers were washed with saturated brine (10 mL), dried, filtered and
the solvent removed in vacuo to yield a colourless oil (87% yield).
Without purification the oil was added to a 50 mL round bottom
flask equipped with a stirrer bar, potassium carbonate (109 mg,
0.8 mmol) and anhydrous DMF (3 mL). Iodomethane was added via
syringe and the reaction stirred for 2 h at ambient temperature. The
reaction was diluted with ethyl acetate (50 mL), transferred to a
1H NMR (500 MHz, CDCl3)
d 9.95 (s, 1H, CHO), 7.60 (d, J 7.7 Hz,
1H, Ar-H), 7.51e7.46 (m, 2H, Ar-H), 7.37 (t, J 7.7 Hz, 1H, Ar-H),
7.31e7.26 (m, 2H, Ar-H), 7.21e7.18 (m, 1H, ArH), 6.99 (dd, J 7.7 and
2.1 Hz, 1H, ArH), 5.95 (s, 1H), 1.31 (s, 3H, CH3), 1.25 (s, 3H, CH3); 13
C
NMR (126 MHz, CDCl3)
d 191.6, 158.3, 156.2, 142.4, 138.1, 130.4,
130.0, 124.6, 124.5, 122.2, 119.5, 118.6, 117.2, 99.3, 83.0, 24.2, 22.2;
FT-IR (thin film):
y
(cmꢂ1) 2979, 1703, 1584, 1481; MS (MALDI)
365.2 [M þ K]þ; HRMS (HNESP) exact mass calculated for C20H22O4
requires m/z 327.1598 found m/z 327.1595 [MþH]þ.
4.1.14. (4,4,5,5-Tetramethyl)-2-(3-vinylphenoxy)phenyl)-1,3-
dioxolane (35)
To a 50 mL flame dried round bottom flask, equipped with a
magnetic stirrer bar, under nitrogen was added methyl-
triphenylphosphonium bromide (2.2 g, 6.13 mmol) in anhydrous
tetrahydrofuran (30 mL) and the flask cooled to 0 ꢀC. Sodium hy-
dride (60% w/w in mineral oil [235 mg, 6.13 mmol]) was added and
the mixture stirred at 0 ꢀC for 10 min 3-(3(4,4,5,5-Tetramethyl-1,3-
dioxolan-2-yl)phenoxy)benzaldehyde 34 (1 g, 3.06 mmol) was
added and the mixture stirred at 0 ꢀC for an additional 30 min.

10
S.P. Bew et al. / Tetrahedron 75 (2019) 130532
separating funnel and washed with water (50 mL) and saturated
brine (30 mL). Drying the organics, the solvent was removed under
reduced pressure and the crude material was isolated in a 92% yield
and used directly in the synthesis of amine 37.
aluminium crimp cap and the reaction mixture was stirred slowly
at room temperature for 18 h. Pyridinium triflate (5 mg,
0.021 mmol, 10 mol%) was added, and the vial was resealed before
being cooled to ꢂ30 ꢀC in a chiller bath. Tert-butyl diazoacetate
(32 mL, 0.23 mmol, 2.2 equiv.) was added via a 100 mL syringe and
4.1.17. Methyl (R)-2-amino-2(3-(3-(4,4,5,5-tetramethyl-1,3-
dioxolan-2-yl)phenoxy)phenyl)acetate (38)
the mixture was stirred at ꢂ30 ꢀC for 16 h. After warming to room
temperature, the solution was filtered through a short plug of silica,
eluting with diethyl ether (3 ꢁ 5 mL). The solvent was removed in
vacuo, and purification via flash column chromatography on silica
gel (eluent: petroleum ether/diethyl ether/dichloromethane 7:2:1;
Rf ¼ 0.26) afforded a white solid whose physicochemical properties
were consistent with those of the title compound 40 (224 mg,
0.22 mmol, 59% yield).
To a 25 mL round bottom flask, equipped with a stirrer bar, was
added under nitrogen 37 (200 mg, 0.39 mmol) and 10% palladium
on carbon (41 mg, 0.04 mmol). Ethyl acetate was added (5 mL) and
the flask sealed with a suba-seal. A balloon of hydrogen was
attached, and the reaction stirred vigorously for 2 h at ambient
temperature. After which it was filtered through a short plug of
silica gel eluting with ethyl acetate (10 mL). The solvent was
removed under reduced pressure affording a colourless oil in an
88% yield. Subsequent physicochemical analysis confirmed this to
be the title compound.
M.p. 78e80 ꢀC; 1H NMR (300 MHz, CDCl3)
d 7.52 (d, J 8.6 Hz, 4H,
Ar-H), 7.34 (s, 2H, Ar-H), 7.33e7.24 (m, 4H, Ar-H), 7.05e6.87 (m,13H,
Ar-H), 5.11 (s, 2H, -CH2Ph), 3.71 (s, 3H, -CO2CH3), 3.40 (d, J 6.7 Hz,
2H, aziridine CeH), 2.99 (d, J 6.7 Hz, 2H, aziridine CeH), 1.33 (s, 18H,
1H NMR (400 MHz, CDCl3)
(m, 5H, Ar-H), 5.87 (s, 1H), 4.51 (s, 1H), 3.63 (s, 3H), 1.85 (br s, 2H,
NH2), 1.23 (s, 3H), 1.17 (s, 3H); 13C NMR (100 MHz, CDCl3)
156.6,
157.8, 141.0, 129.0, 128.7.0, 120.5, 120.4, 118.1, 117.1, 116.4, 116.0, 98.4,
81.8, 57.4, 51.4, 23.25, 21.15; FT-IR (thin film):
(cmꢂ1) 3389 (NH2),
d
7.27e7.21 (M, 3H, Ar-H), 7.19e6.83
-C(CH3)3), 1.17 (s, 18H, -C(CH3)3); 13C NMR (126 MHz, CDCl3)
d 167.1,
165.65, 156.2, 150.7, 148.0, 146.5, 145.4, 136.7, 132.0, 130.6, 129.6,
128.5, 128.3, 128.27, 128.2, 125.6, 123.2, 123.15, 123.0, 120.95, 117.7,
117.6, 116.8, 116.4, 81.4, 80.4, 75.35, 52.2, 47.4, 47.0, 28.7, 27.9; FT-IR
d
y
(thin film): y
(cmꢂ1) 2979 (CeH), 1721 (C]O), 1582, 1494, 1423,
2978 (CeH), 1740 (ester and aldehyde C]O), 1585, 1484, 1253, 1157,
1063; MS (MALDI-TOF) m/z 424.3 [MþK]þ; HRMS (HNESP) exact
mass calculated for C22H28O5N requires m/z 386.1962, found m/z
386.1964 [MþH]þ.
1368, 1334, 1260, 1216, 1161, 1043, 978, 846; MS (MALDI-TOF) m/z
1005.25 [M]þ; HRMS (NESP) exact mass calculated for C61H72N3O11
requires m/z 1022.5161, found m/z 1022.5169 [M þ NH4]þ.
4.1.20. rac, cis-tert-Butyl 3-(4-(2-(benzyloxy)-3-(4-
4.1.18. Methyl 4-(benzyloxy)-3,5-bis(4-formylphenoxy)benzoate
(39)
formylphenoxy)-5-(methoxycarbonyl)phenoxy)phenyl)-1-(2-(tert-
butoxy)phenyl)aziridine-2-carboxylate (41)
A 250 mL round-bottom flask was charged with a solution of 22
(3.01 g, 7.65 mmol, 1 equiv.) in N,N-dimethylformamide (50 mL)
A by-product was isolated during the flash column chroma-
tography (Rf ¼ 0.23); this was identified as rac, cis-tert-butyl 3-(4-
(2-(benzyloxy)-3-(4-formylphenoxy)-5-(methoxycarbonyl)phe-
noxy)phenyl)-1-(2-(tert-butoxy)phenyl)aziridine-2-carboxylate 41
(64 mg, 0.087 mmol, 23% yield; Rf ¼ 0.23).
under
a nitrogen atmosphere. Potassium carbonate (712 mg,
11.5 mmol, 1.5 equiv.) was added in one portion, followed by the
addition of benzyl bromide (0.91 mL, 7.65 mmol,1 equiv.) via a 2 mL
syringe. The mixture was stirred at room temperature for 18 h
before being transferred to a 250 mL separating funnel containing
1 M aqueous hydrochloric acid (100 mL). The organics were
extracted with ethyl acetate (3 ꢁ 75 mL). The combined organic
layers were washed with water (3 ꢁ 100 mL) and subsequently
brine (100 mL). The organic layer was dried over magnesium sul-
fate, filtered, and the solvent removed in vacuo. Purification via
flash column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate 30%; Rf 0.38) afforded a pale-yellow solid whose
physicochemical characteristics were consistent with those of the
title compound 39 (3.21 g, 6.64 mmol, 87% yield).
1H NMR (500 MHz, CDCl3)
d 9.86 (s, 1H, -CHO), 7.77 (d, J 8.8 Hz,
2H, Ar-H), 7.49e6.89 (m,17H, Ar-H), 5.04 (s, 2H, -CH2Ph), 3.76 (s, 3H,
-CO2CH3), 3.42 (d, J 6.7 Hz, 1H, aziridine CeH), 3.00 (d, J 6.7 Hz, 1H,
aziridine CeH), 1.50 (s, 9H, -C(CH3)3), 1.17 (s, 9H, -C(CH3)3); 13C NMR
(126 MHz, CDCl3)
d 190.8, 167.0, 165.4, 162.6, 155.9, 151.0, 148.2,
148.0, 146.4, 146.2, 136.2, 132.0, 131.6, 131.5, 131.0, 129.7, 128.3,
128.29,126.0,123.1,123.08, 120.9,118.7,118.0,117.7,116.8, 81.4, 80.4,
75.4, 52.4, 47.4, 46.9, 28.7, 27.9; FT-IR (thin film):
y
(cmꢂ1) 3063
(CeH), 2978 (CeH), 1724 (ester C]O), 1699 (aldehyde C]O), 1580,
1504, 1491, 1452, 1422, 1392, 1368, 1333, 1306, 1223, 1157, 1040,
1005; MS (MALDI-TOF) m/z 782.1 [MþK]þ; HRMS (HNESP) exact
mass calculated for C45H46NO9 requires m/z 744.3167, found m/z
744.3165 [MþH]þ.
M.p. 80e82 ꢀC; 1H NMR (400 MHz, CDCl3)
d 9.87 (s, 2H, -CHO),
7.79 (d, J 8.8 Hz, 4H, Ar-H), 7.59 (s, 2H, Ar-H), 7.15e7.07 (m, 3H, Ar-
H), 6.97e6.94 (m, 6H, Ar-H), 4.98 (s, 2H, -CH2Ph), 3.80 (s, 3H,
-OCH3); 13C NMR (100 MHz, CDCl3)
d
190.6, 165.1, 162.2, 148.5, 147.0,
135.75, 132.03, 131.8, 128.4, 128.3, 128.1, 126.4, 120.3, 116.9, 75.6,
52.5; FT-IR (thin film):
(cmꢂ1) 3069 (CeH), 2956 (CeH), 2835
4.1.21. Methyl 4-(benzyloxy)-3,5-bis(4-(4,4,5,5-tetramethyl-1,3-
dioxolan-2-yl)phenoxy)benzoate (42)
y
A 100 mL two-neck round-bottom flask was charged with a
solution of methyl 4-(benzyloxy)-3,5-bis(4-formylphenoxy)benzo-
ate 39 (1.0 g, 2.55 mmol, 1 equiv.) in dry toluene (40 mL). The flask
was fitted with a Dean-Stark apparatus and reflux condenser under
a nitrogen atmosphere. Pinacol (692 mg, 5.86 mmol, 2.3 equiv.) and
para-toluenesulfonic acid (20 mg, 0.11 mmol, 5 mol%) were added,
and the solution heated at reflux for 6 h. After cooling to room
temperature, triethylamine (0.1 mL, 0.72 mmol, 0.3 equiv.) was
added via a 1 mL syringe and the solution stirred for a further
30 min before the solvent was removed in vacuo. Purification via
flash column chromatography on silica gel (eluent: petroleum
ether/diethyl ether 1:1; Rf ¼ 0.58) afforded a white solid whose
physicochemical properties were consistent with those of the title
compound 42 (1.50 g, 2.19 mmol, 86% yield).
(CeH), 2745 (CeH), 1724 (d) (ester and aldehyde C]O), 1602, 1503,
1422, 1337, 1229, 1157; MS (MALDI-TOF) m/z 505.0 [MþNa]þ,
520.96 [MþK]þ; HRMS (NESP) exact mass calculated for
C
29H22O7Na requires m/z 505.1258, found m/z 505.1250 [MþNa]þ.
4.1.19. rac, cis-Di-tert-butyl 3,3'-(((2-(benzyloxy)-5-
(methoxycarbonyl)-1,3-phenylene)bis(oxy))bis(4,1-phenylene))
bis(1-(2-(tert-butoxy)phenyl)aziridine-2-carboxylate) (40)
A 5 mL microwave vial containing 4 Å molecular sieves was
flame-dried and cooled under a flow of nitrogen. A solution of
methyl
4-(benzyloxy)-3,5-bis(4-formylphenoxy)benzoate
39
(100 mg, 0.21 mmol, 1 equiv.) and 2-tert-butoxyaniline (67 mg,
0.40 mmol, 1.95 equiv.) in dry chloroform (1.5 mL) was added, along
with a magnetic stirrer bar. The vial was sealed with a PTFE-lined
M.p. 132e134 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.47 (d, J 8.7 Hz,

S.P. Bew et al. / Tetrahedron 75 (2019) 130532
11
4H, Ar-H), 7.41 (s, 2H, Ar-H), 7.24e7.12 (m, 5H, Ar-H), 6.88 (d, J
116.45, 116.4, 99.5, 82.8, 75.3, 24.5, 22.3; FT-IR (thin film): y )
(cmꢂ1
8.7 Hz, 4H, Ar-H), 5.90 (s, 2H, -CH- pin.), 5.04 (s, 2H, -CH2Ph), 3.73 (s,
2977 (CeH), 2936 (CeH), 2864 (CeH), 1696 (C]O), 1614, 1579,
1507, 1435, 1377, 1325, 1222, 1150, 1119, 1075, 1044; MS (MALDI-
TOF) m/z 691.44 [MþK]þ; HRMS (HNESP) exact mass calculated for
3H, -CO2CH3), 1.26 (s, 12H, -C(CH3)2-), 1.22 (s, 12H, -C(CH3)2-); 13C
NMR (126 MHz, CDCl3)
128.5, 128.3, 128.15, 128.1, 125.7, 117.7, 117.4, 99.6, 82.7, 75.3, 52.3,
24.5, 22.3; FT-IR (thin film):
(cmꢂ1) 2980 (CeH), 2932 (CeH), 2877
d 165.7, 157.3, 150.3, 145.9, 136.5, 134.8,
C
40H48O8N requires m/z 670.3374, found m/z 670.3390 [M þ NH4]þ.
y
(CeH), 1727 (C]O), 1614, 1583, 1504, 1453, 1425, 1391, 1380, 1373,
1332, 1222, 1157, 1075, 1040, 1006; MS (MALDI-TOF) m/z 681.7;
HRMS (HNESP) exact mass calculated for C41H50O9N requires m/z
700.3480, found m/z 700.3496 [M þ NH4]þ.
4.1.23. 4,4'-((2-(Benzyloxy)-5-vinyl-1,3-phenylene)bis(oxy))
bis((dimethoxymethyl)benzene) (44)
A 250 mL round-bottom flask under a nitrogen atmosphere was
charged with methyl triphenylphosphonium bromide (1.09 g,
3.06 mmol, 4 equiv.) and tetrahydrofuran (40 mL). The suspension
was stirred while being cooled to 0 ꢀC in an ice bath before the
addition of sodium hydride (60% in mineral oil, 122 mg, 3.06 mmol,
4 equiv.). After 1 h, a solution of 4-(benzyloxy)-3,5-bis(4-(dime-
thoxymethyl)phenoxy)benzaldehyde 43 (500 mg, 0.77 mmol, 1
equiv.) in tetrahydrofuran (10 mL) was added dropwise to the flask
via a 20 mL syringe, and the resulting mixture stirred at 0 ꢀC for a
further 3 h or until complete disappearance of the starting material
by thin layer chromatography (eluent: petroleum ether/ethyl ace-
tate 20%). Diethyl ether (75 mL) was added, and the mixture
transferred to a 500 mL separating funnel containing cold distilled
water (100 mL). The aqueous phase was extracted with diethyl
ether (2 ꢁ 100 mL) and the combined organic layers washed with
brine (150 mL) before being dried over magnesium sulfate, filtered,
and the solvent removed in vacuo. Purification via flash column
chromatography on silica gel (eluent: petroleum ether/ethyl ace-
tate 20%; Rf ¼ 0.53) afforded a white solid whose physicochemical
properties were consistent with those of the title compound 44
(379 mg, 0.58 mmol, 76% yield).
4.1.22. (4-(Benzyloxy)-3,5-bis(4-(4,4,5,5-tetramethyl-1,3-dioxolan-
2-yl)phenoxy)phenyl) aldehyde (43)
4.1.22.1. Part 1. To a flame-dried 250 mL round-bottom flask was
added lithium aluminium hydride (118 mg, 3.11 mmol, 2.5 equiv.)
and dry tetrahydrofuran (40 mL) under a nitrogen atmosphere. The
mixture was cooled to ꢂ15 ꢀC using an salt ice bath before a solu-
tion of methyl 4-(benzyloxy)-3,5-bis(4-(4,4,5,5-tetramethyl-1,3-
dioxolan-2-yl)phenoxy)benzoate 42 (2.62 g, 4.56 mmol, 1 equiv.)
in tetrahydrofuran (15 mL) was added dropwise via a 20 mL sy-
ringe. The mixture was allowed to warm to 0 ꢀC and stirred for 2 h.
On complete disappearance of the starting material by thin layer
chromatography (petroleum ether/diethyl ether 1:1), ethyl acetate
(50 mL) and 1 M aqueous sodium hydroxide (50 mL) were added
simultaneously in small portions while maintaining the tempera-
ture at 0 ꢀC. The reaction mixture was transferred to a 500 mL
separating funnel and the aqueous phase extracted with ethyl ac-
etate (2 ꢁ 75 mL). The combined organic phases were washed with
brine (150 mL), dried over magnesium sulfate, filtered, and the
solvent removed in vacuo affording a colourless oil whose physi-
cochemical properties were consistent with those of the title
compound (2.42 g, 4.42 mmol, 97% yield); no further purification
was required.
M.p. 116e118 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.39 (d, J 8.6 Hz,
4H, Ar-H), 7.14e7.07 (m, 5H, Ar-H), 6.90 (d, J ¼ 8.6 Hz, 4H, Ar-H), 6.74
(s, 2H, Ar-H), 6.40 (dd, J 17.5, 11.0 Hz, 1H, -CH]CH2), 5.90 (s, 2H,
-CH- pin.), 5.45 (dd, J 17.5, 0.4 Hz, 1H, -CH]CH2), 5.08 (d, J ¼ 11.0 Hz,
1H, -CH]CH2), 4.93 (s, 2H, -CH2Ph), 1.27 (s, 12H, -CH(CH3)2-), 1.22
Rf ¼ 0.21 (eluent: petroleum ether/diethyl ether 1:1); 1H NMR
(500 MHz, CDCl3)
d
7.46 (d, J 8.6 Hz, 4H, Ar-H), 7.22e7.15 (m, 5H, Ar-
(s, 12H, -CH(CH3)2-); 13C NMR (126 MHz, CDCl3)
d
157.8, 150.4, 141.7,
136.9, 135.3, 134.3, 133.8, 128.5, 128.2, 128.0, 127.95, 117.5, 114.4,
114.2, 99.7, 82.7, 75.3, 24.5, 22.3; FT-IR (thin film):
(cmꢂ1) 2983
H), 6.97 (d, J 8.6 Hz, 4H, Ar-H), 6.73 (s, 2H, Ar-H), 5.97 (s, 2H, -CH-
pin.), 5.01 (s, 2H, -CH2Ph), 4.48 (s, 2H, -CH2OH), 1.33 (s, 12H,
-C(CH3)2-), 1.29 (s, 12H, -C(CH3)2-); 13C NMR (126 MHz, CDCl3)
y
(CeH), 2928 (CeH), 2855 (CeH), 1610, 1569, 1503, 1428, 1410, 1390,
1321, 1228, 1155, 1076, 1031, 990; MS (MALDI-TOF) m/z 689.69
[MþK]þ; HRMS (HNESP) exact mass calculated for C41H50O7N re-
quires m/z 668.3582, found m/z 668.3581 [M þ NH4]þ.
d
157.7, 150.8, 141.1, 137.2, 137.0, 134.5, 128.6, 128.3, 128.1, 128.1,
117.9, 114.4, 99.8, 82.8, 75.4, 64.5, 24.6, 22.3; FT-IR (thin film):
y
(cmꢂ1) 3458 (OeH), 2984 (CeH), 2932 (CeH), 2877 (CeH), 1610,
1586, 1507, 1435, 1370, 1322, 1219, 1154, 1075, 1034, 989; MS
(MALDI-TOF) m/z 693.12 [MþK]þ; HRMS (HNESP) exact mass
4.1.24. 4,4'-(2-(Benzyloxy)-5-vinyl-1,3-phenylene)bis(oxy)
dibenzaldehyde (44)
calculated for
C40H50O8N requires m/z 672.3530, found m/z
672.3531 [M þ NH4]þ.
A 5 mL microwave vial was charged with a colourless solution of
4,4'-((2-(benzyloxy)-5-vinyl-1,3-phenylene)bis(oxy))bis((dime-
thoxymethyl)benzene) 43 (50 mg, 0.08 mmol, 1 equiv.) in tetrahy-
drofuran (1 mL). 1 M aqueous hydrochloric acid (1 mL) was added,
and the solution was heated at 50 ꢀC with stirring for 3 h. On
complete disappearance of the starting material by thin layer
chromatography (eluent: petroleum ether/ethyl acetate 20%), the
organic solvent was removed in vacuo and the residue extracted
with dichloromethane (3 ꢁ 5 mL). The combined organic layers
were washed with brine (20 mL), dried over magnesium sulfate,
filtered, and the solvent removed in vacuo. Purification via flash
column chromatography on silica gel (eluent: petroleum ether/
diethyl ether 50%; Rf ¼ 0.31) afforded a white solid whose physi-
cochemical characteristics were consistent with those of the title
compound 44 (31 mg, 0.069 mmol, 90% yield).
4.1.22.2. Part 2. A 250 mL round-bottom flask was charged with a
solution of 4-(benzyloxy)-3,5-bis(4-(dimethoxymethyl)phenoxy)
benzyl alcohol (447 mg, 0.68 mmol,
1 equiv.) in anhydrous
dichloromethane (50 mL) under a nitrogen atmosphere. Activated
manganese dioxide (1.19 g, 13.7 mmol, 20 equiv.) was added in
small portions and the mixture stirred at room temperature for
18 h. On confirmation of the complete disappearance of starting
material by thin layer chromatography (eluent: petroleum ether/
ethyl acetate 20%), the mixture was filtered through celite and the
solvent removed in vacuo. Purification via flash column chroma-
tography on silica gel (eluent: petroleum ether/ethyl acetate 20%;
Rf ¼ 0.38) afforded a white solid whose physicochemical charac-
teristics were consistent with those of the title compound 43
(307 mg, 0.47 mmol, 69% yield).
M.p. 101e103 ꢀC; 1H NMR (400 MHz, CDC3)
d 9.92 (s, 2H, -CHO),
7.82 (d, J 8.6 Hz, 4H, Ar-H), 7.16e6.94 (m, 11H, Ar-H), 6.59 (dd, J 17.5,
11.0 Hz, 1H, -CH]CH2), 5.65 (d, J 17.5 Hz, 1H, -CH]CH2), 5.29 (d, J
11.0 Hz, 1H, -CH]CH2), 4.92 (s, 2H, -CH2Ph); 13C NMR (100 MHz,
M.p. 118e120 ꢀC; 1H NMR (500 MHz, CDCl3)
d
9.70 (s, 1H, -CHO),
7.43 (d, J 8.6 Hz, 4H, Ar-H), 7.19e7.13 (m, 7H, Ar-H), 6.92 (d, J 8.6 Hz,
4H, Ar-H), 5.91 (s, 2H), 5.12 (s, 2H), 1.27 (s, 12H, -C(CH3)2-), 1.23 (s,
12H, -C(CH3)2-); 13C NMR (126 MHz, CDCl3)
d
189.7, 156.9, 151.3,
CDCl3)
d
190.7, 162.7, 148.75, 142.8, 136.1, 134.7, 132.0, 131.5, 128.2,
146.8, 136.4, 135.4, 132.0, 128.5, 128.3, 128.27, 128.22, 118.1, 118.05,
128.16, 117.0, 116.7, 115.4, 75.6; FT-IR (thin film):
y
(cmꢂ1) 3070,

12
S.P. Bew et al. / Tetrahedron 75 (2019) 130532
3033, 2834, 2741, 1696 (C]O), 1600, 1585, 1569, 1501, 1454, 1430,
1408, 1321, 1225, 1154, 1104, 1057, 1026; MS (MALDI-TOF) m/z
473.32 [MþNa]þ; HRMS (HNESP) exact mass calculated for
to thank Dr Brian Cox of Novartis and Uniqsis Ltd and, in particular,
Dr Paul Pergande for the loan and help with translating this
chemistry to flow on their FlowSyn reactor.
C
29H26O5N requires m/z 468.1805, found m/z 468.1802 [M þ NH4]þ.
Appendix A. Supplementary data
4.1.25. tert-Butyl 3-(4-(2-(benzyloxy)-3-(4-formylphenoxy)-5-
vinylphenoxy)phenyl)-1-(2-tert-butoxyphenyl)aziridine-2-
carboxylate (46)
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2019.130532.
A 5 mL microwave vial containing crushed 4 Å molecular sieves
was flame-dried and cooled under nitrogen. The vial was charged
with 4,4'-((2-(benzyloxy)-5-vinyl-1,3-phenylene)bis(oxy))diben-
zaldehyde 45 (100 mg, 0.22 mmol, 1 equiv.) and a solution of 2-tert-
butoxyaniline (36 mg, 0.22 mmol, 0.98 equiv.) in chloroform (1 mL).
The mixture was stirred at room temperature for 16 h. Pyridinium
triflate (5 mg, 0.02 mmol, 10 mol%) was added, and the vial sealed
with a PTFE-lined aluminium crimp cap. Tert-butyl diazoacetate
References
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(31 mL, 0.22 mmol, 1 equiv.) was added dropwise via syringe. The
mixture was stirred at room temperature for a further 16 h and
filtered through a short plug of silica gel, eluting with diethyl ether
(3 ꢁ 5 mL). The solvent was removed in vacuo to afford a brown oil.
Purification via flash column chromatography on silica gel (eluent:
petroleum ether/diethyl ether/dichloromethane (8:1:1); Rf 0.20)
afforded a pale red liquid whose physicochemical properties were
consistent with those of the title compound 46 (46 mg,
0.025 mmol, 49%).
1H NMR (500 MHz, CDCl3)
d 9.91 (s, 1H -CHO), 7.81 (d, J 8.7 Hz,
2H, Ar-H), 7.54 (d, J 8.7 Hz, 2H, Ar-H), 7.26e6.83 (m, 15H, Ar-H), 6.49
(dd, J 10.9, 17.5 Hz, 1H, -CH]CH2), 5.58 (d, J 17.5 Hz, 1H, -CH]CH2),
5.22 (d, J 10.9 Hz, 1H, -CH]CH2), 5.00 (s, 2H, -CH2Ph), 3.48 (d, J
6.7 Hz, 1H, aziridine -CH-), 3.05 (d, J 6.7 Hz, 1H, aziridine -CH-), 1.38
(s, 9H, -C(CH3)3), 1.23 (s, 9H, -C(CH3)3); 13C NMR (100 MHz, CDCl3)
d
191.0, 167.2, 163.2, 156.5, 151.4, 148.6, 148.1, 146.6, 142.0, 136.8,
135.3, 134.4, 132.15, 131.4, 130.7, 129.7, 128.5, 128.4, 128.3, 123.3(2),
123.2, 121.1, 117.8, 116.7, 115.3, 115.0, 114.9, 81.5, 80.5, 75.65, 47.55,
47.2, 28.9, 28.1; FT-IR (thin film):
y
(cmꢂ1) 3065, 3033, 2976, 2930,
2733, 2250, 1744 (ester C]O), 1696 (aldehyde C]O), 1596, 1584,
1568,1490,1452,1428,1407,1392,1367,1319,1225,1155,1111,1028;
HRMS (HNESP) exact mass calculated for C45H46NO7 requires m/z
712.3269, found m/z 712.3265 [MþH]þ.
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[18] Crystallographic Data (Excluding Structure Factors) for the Structures in This
Paper Have Been Deposited with the Cambridge Crystallographic Data Centre
as Supplementary Information Witht the Following Numbers CCDC 1895463
(22), CCDC 1895459 (39) and CCDC 1895499 (43). Copies of the Data Can Be
Obtained, Free of Charge, on Application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: þ44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.Uk).
Acknowledgments
The authors would like to acknowledge the financial assistance
of the UEA, Novartis, EPSRC and the EPSRC UK National Mass
Spectrometry Facility, Swansea University. The authors would like