The attempted stereoselective synthesis of chiral 2,2′-biindoline

Article abstract of DOI:10.1016/j.tet.2010.06.035

The attempted first stereoselective synthesis of 2,2′-biindoline using a metathesis-Sharpless asymmetric dihydroxylation strategy results in the synthesis of the heterocycle in poor to modest stereoselectivity. Attempts to improve the ee by varying the he

Full text of DOI:10.1016/j.tet.2010.06.035

Tetrahedron 66 (2010) 6965e6976
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The attempted stereoselective synthesis of chiral 2,20-biindoline
*
Mary J. Gresser, Steven M. Wales, Paul A. Keller
Centre for Medicinal Chemistry, School of Chemistry, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia
a r t i c l e i n f o
a b s t r a c t
The attempted first stereoselective synthesis of 2,20-biindoline using a metathesis-Sharpless asymmetric
dihydroxylation strategy results in the synthesis of the heterocycle in poor to modest stereoselectivity.
Attempts to improve the ee by varying the heteroatom protecting groups in key intermediates did not
enhance the outcome of the Sharpless AD reaction. Therefore a limitation of this AD reaction is the use of
1,4-substituted but-2-enes where these substituents are ortho-substituted aromatics.
Article history:
Received 1 March 2010
Received in revised form 26 May 2010
Accepted 14 June 2010
Available online 18 June 2010
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Keywords:
Biindoline
Metathesis
Sharpless AD
Chiral biamines
Helical chiral ligands
1. Introduction
modulated by a range of substituents ‘R’, including the presence of
fused rings. Importantly, an appropriate synthetic strategy towards
Chiral biamine compounds are commonly used as ligands in
stereoselective metal-catalysed reactions, including Michael addi-
tions, biaryl couplings and asymmetric dihydroxylations to name
just a few.1 We are interested in chiral ligand designs based on helix
sense discrimination and ligand types of appeal include biphos-
phines, biarsines, biamines and helical ligands that possess a mix-
ture of heteroatoms. Our general target structures are encapsulated
by 2 (Fig. 1) where the helix is defined by two stereogenic atoms,
flanked by metal co-ordinating heteroatoms, thus forming an arc of
helicity. The helical groove depth and degree of twist could be
these structures should not only be highly stereoselective, but
should allow articulation to produce different ring sizes, fused-ring
structures and a range of substituted ligands stereoselectively, and
in an efficient manner.
The importance of the indoline structure has long been recog-
nised with reference to its place in natural product chemistry, drug
design and development and in industry as a key element in cat-
alysts. Despite this illustrious history, there has been surprisingly
little investigation into the 2,20-biindoline structure 42deven more
surprising is the lack of any reporting of the stereoselective syn-
thesis of 4 or related compounds that contain 4 as a substructure. In
this paper, we report the first attempted stereoselective synthesis
of the parent 2,20-biindoline 4 starting from achiral substrates and
utilising Sharpless asymmetric dihydroxylation as the key reaction
for the introduction of the chiral elements.
OH
R
R
R
R
OH
3
1
2. Results
R'
R'
* *
X
X
R
We, and others, have previously reported
a self-meta-
N
N
R
H
H
thesisddihydroxylation strategy for the stereoselective synthesis
of 2,20-bipyrrolidine3 and 2,20-bistetrahydrofuran.4 Here we utilise
the same strategy (Fig. 1), starting with the protection of 2-allyla-
niline20 to produce 6 in 88% yield (Scheme 1).5 Olefin metathesis of
6 using Grubbs II catalyst in CH2Cl2 at reflux yielded the dimer 7
(61%) as a 92:8 mixture of the E/Z isomersda single recrystallisa-
tion from hexanes increased the ratio to E/Z 99:1 in 37% yield. The
geometric isomers were unable to be separated by column
2
4
Figure 1. Metathesisdasymmetric dihydroxylation strategy towards the synthesis of
bipyrrolidines and biindolines.
* Corresponding author. Tel.: þ61 2 4221 4692; fax: þ61 2 4221 4287; e-mail
address: keller@uow.edu.au (P.A. Keller).
0040-4020/$ e see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.035

6966
M.J. Gresser et al. / Tetrahedron 66 (2010) 6965e6976
chromatography, however, the stereochemical outcome was de-
termined by integral analysis of the 1H NMR spectrum, in which the
cis and trans signals from the methyl and methylene protons were
baseline resolved. All attempts at this metathesis reaction using
Grubbs’ I resulted in significantly poorer selectivity in the E/Z ratios,
at best 70:30.
Having shown the feasibility of the strategy, we attempted the
analogous reaction starting with the o-allylphenol 12 (Scheme 2).
This would lead to the intermediate 13 where the phenolic oxygen
has been converted into a triflate group, which would allow a Pd-
catalysed cyclisation to yield the (2S,20S)-biindoline.
OH
OTf
NH2
R
NHBoc
HN
(ii)
NH2
13
OTf
NHBoc
NHBoc
12
5
R = H
(i)
7
6 R = Boc
(iii)
N
N
H
H
NHBoc OMs
NHBoc OH
(iv)
4
Scheme 2. Strategy to biindolines using phenolic substituents.
OMs
NHBoc
OH
(S,S)-9
(S,S)-8
The phenol 12 was protected using standard procedures
(Scheme 3) and the resulting products subjected to Grubbs’ I me-
tathesis conditions to give the olefin in 81% yield with an E/Z ratio of
5.2:1. Dihydroxylation under standard conditions with ADmix
(v)
(vi)
N
N
N
H
N
H
Boc Boc
a
gave the (S,S)-diol 15 in 15% yield with 64% ee. The same pro-
(R,R)-4
(R,R)-10
cedure with longer reaction times (91 h) gave a 64% yield with
a 33% ee. Use of ADmix
b
gave a 69% yield with a 91% ee.
Scheme 1. The attempted stereoselective synthesis of chiral 2,20-biindoline 4. Illus-
trated is the example of the synthesis of the R,R-biindoline. (i) BocO2, Et3N, Et2O,
0
ꢀC/rt, 4.5 h, 88%; (ii) Grubbs’ II, CH2Cl2,
from hexanes, 37% (E/Z 99:1); (iii) ADmix
30 min, (S,S)-8 34%, ee 50%, ADmix
D
a
, 7 h, 61% (E/Z 92:8)drecrystallisation
, methanesulfonamide, 1:1 tBuOH/H2O,
: (R,R)-8 31%, ee 56%; (iv) MsCl, Et3N, CH2Cl2,
OR
OBn
(ii)
b
20 min, (S,S)þmeso-9 98%, (R,R)þmeso-9 92%; (v) NaH, DMF, 0 ꢀC 24 h, (S,S)-10 74%, (R,
R)-10 47%; (vi) TFA, CH2Cl2, 12 h, (S,S)-11 82%, (R,R)-11 62%.
OBn
12
13
14
R = H
(i)
R = Bn
(iv)
(iii)
The Sharpless asymmetric dihydroxylation of E-olefin 7 was
performed with ADmix
50% ee. Reaction with ADmix
a
affording the (S,S)-diol 8 in 34% yield and
gave the (R,R)-diol 8 in 31% yield and
OBn
OH
OBn
OH
b
56% ee.6 The poor outcome of the dihydroxylation, in terms of both
conversion and enantioselectivity, is surprising given that the
substrate contains the preferred aromatic group for the binding
pocket.7 This result can, at least in part, be rationalized by the ex-
treme hydrophobicity of the substrate, which limited its solubility
in the polar reaction medium. Additionally, it is possible that the
Boc substituent was too large to be accommodated by the binding
pocket,8 which encouraged stereo-indiscriminative binding at the
less hindered equatorial oxygens.9 Attempts to optimise this
dihydroxylation reaction did not improve the outcome.
Although these results compromise the stereoselective synthe-
sis and require further examination, we first needed to illustrate the
overall synthetic strategy and therefore continued through with
the synthesis of the 2,20-biindoline. Therefore, the diol 8, as a mix-
ture of the enantiomerically enriched (S,S) and meso epimers,10 was
subjected to standard mesylation conditions giving 9 (S,Sþmeso,
98%; R,Rþmeso, 92%) as a mixture of diastereomers. The mixtures
were then treated with excess NaH in THF yielding the biindoline
10 (S,S, 74%, ee 67%; R,R, 47%, ee 55%), and separately. the meso-
biindoline 10.11 The mono cyclized indoline 11 (20%) (Fig. 2) was
also isolated along with a small quantity of an unknown material.
Removal of the Boc protecting group with excess TFA in CH2Cl2
afforded the biindoline 4 (S,S, 82%; R,R, 62%).
OH
(S,S)-15
OBn
OH
OBn
(R,R)-15
Scheme 3. Metathesis and asymmetric dihydroxylation using phenolic starting
materials.
Given the unsatisfactory results of the dihydroxylation reaction,
we embarked on an investigation to find the most suitable ortho-
substituents to use in such reactions. This required the synthesis of
the monomeric starting materials, which were then subjected to
the metathesis reactions before treatment of the olefins to Sharp-
less reaction conditions. The results of these investigations are
summarised in Tables 1 and 2.
The results of the metathesis reactions are surprisingly variable,
with the E/Z ratios generally better using Grubbs’ II catalyst. Al-
though further optimisation of relevant reactions could proceed,
the more important results were the outcome of the dihydrox-
ylation reactions. The variations in the O-substituted olefins (Table
2, entries 1e6) and those containing aromatic N-substituents (Table
2, entries 7e9) encompassed a range of steric intrusion (both large
and small) and electron donating and withdrawing character. The
results were surprisingly variable both in terms of yield and in
particular, enantioselectivity and would not allow the progression
of a reasonable stereoselective synthesis. The most reasonable
conclusion to draw was that the double ortho substitution was
imposing excessive steric bulk and was not allowing the substrate
to fit into the binding pocket of the chiral ligand. To test this steric
argument, we synthesised the aromatic dimethoxy derivatives with
the substituents placed ortho, meta and para to the butenyl chain
(Table 2, entries 10e12) such that there was a decreasing steric
influence on the substrate when binding to the chiral catalyst. In
OMs
N
Boc
HN
Boc
11
Figure 2. The structure of the minor side product assigned based 1H and 13C NMR, MS
and HRMS analyses.
this series, for both ADmix a and b, there was an increase in yield

M.J. Gresser et al. / Tetrahedron 66 (2010) 6965e6976
6967
Table 1
Entry
R
Monomer
Olefin
Grubbs’ I
Grubbs’ II
Mol %
Time (h)
Yielda
%
E/Zb
Mol %
Time (h)
Yielda
%
E/Zb
1
2
3
4
5
OBn
OPMB
OAc
OTf
OTBS
14
17
18
19
20
15
29
30
31
32
d
33e
7
34
35
6.7
5
5
5
5
4.5
23
15
15
66
d
25
3
d
d
d
19
7
81
51
85
88
85
d
5.2:1
5:1
4:1
3.8:1
4.3:1
5
5
5
5
5
5
d
10
10
5
5
5
5
d
d
3
d
d
5
26
23
66
66
66
7.5
d
7
93
71
77
75
95c
95c
d
7:1
7.1:1
8:1
9:1
8.4:1
7:1
6
7
8
9
OH
13
6
21
22
10
10
d
d
d
5
50
76
d
9:1
1.6:1
d
d
NHBoc
NHAc
NO2
61
73
26
23
60c
73c
d
11.5:1
E only
43:1
10:1
5.6:1
5.5:1
d
17
7
d
d
d
d
20
19
24
d
d
25
d
d
23
10
o-OMe
23
36
81
91
63
97
69
89
4.4:1
4.5:1
4.5:1
6.2:1
4.8:1
4.7:1
5
11
12
13
m-OMe
p-OMe
H
24
25
26
37
38
39
2.5
2.5
5
2.5
2.5
d
15
4.5
24
18
d
d
0
d
d
d
14
15
Me
Br
27
28
40
d
16c
d
41d
6.2:1
a
Isolated yield.
b
c
Determined by 1H NMR.
Final yield determined by 1H NMR.
d
A mixture of olefins was produced, tentatively assigned as E-1,4-di(2-bromophenyl)-2-butene 41, Z-1,4-di(2-bromophenyl)-2-butene, E-1,4-di(2-bromophenyl)-1-bu-
tene, E-1,5-di(2-bromophenyl)-2-pentene, E-3-(2-bromophenyl)-1-phenylpropene and E-1-(2-bromophenyl)-3-phenylpropene in a 6.3:1:1.2:1.1:1:1.2 ratio as determined
by 1H NMR analysis.
e
Olefin synthesised by deprotection of 32.
Table 2
AD mix α/β
methanesulfonamide
R
OH
R
t BuOH:H O
2
R
OH
R
Entry
R
Olefin
Diol
ADmix
a
ADmix b
a
b
a
b
Time (h)
Yield %
ee %
Time (h)
Yield %
ee %
1
2
3
4
5
6
7
8
OBn
OPMB
OAc
OTf
OTBS
OH
NHBoc
NHAc
NO2
o-OMe
m-OMe
p-OMe
H
15
29
30
31
32
33
7
34
35
36
37
38
39
40
16
42
43
44
45
46
8
47
48
49
50
51
52
53
91
40
24
24
24
24
90
24
24
24
24
24
24
24
64
Trace
0
25
13
0
30
d
37
40
24
24
24
24
90
24
24
24
24
24
24
24
69
Trace
0
58
31
0
91
d
d
8
d
1.4
23
d
14
d
56
d
58
40
76
87
95
70
34
0
31
d
31
0
9
18
52
77
90
88
65
44
34
73
85
93
62
45
37
86
96
84
45
10
11
12
13
14
Me
a
Isolated yield.
Determined by chiral HPLC.
b
and ee as the dimethoxy substituents were further away from the
butenyl chain. To add support to our steric argument, we tested the
aromatic unsubstituted (Table 2, entry 13) and the di-o-methyl
substituted (Table 2, entry 14) derivatives, the latter being a rela-
tively electronically neutral and small moiety. The former returned
excellent yields, comparable to those reported27 and ee values
whereas the latter, with just a small steric intrusion, already started
to induce a decrease in yield in ee. Therefore, there is strong
evidence that steric hinderance is playing a significant role in the
outcome of these dihydroxylation reactions.
3. Conclusion
We have shown that the metathesisddihydroxylation strategy
can be extended from the synthesis of 2,20-bipyrrolidines to the
synthesis of 2,20-biindolines, however, it is not
a valid

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M.J. Gresser et al. / Tetrahedron 66 (2010) 6965e6976
stereoselective synthesis with poor ee returns during the dihy-
droxylation reactions. We suggested that the steric intrusion of the
two aromatic ortho substituents are responsible and that it is suf-
ficiently general to say that the Sharpless AD reactions are not
suitable conditions for any allylic bis(di-ortho-substituted aro-
matic) systems. We are currently investigating an alternative syn-
thetic strategy towards the key intermediate diols, which avoids
the Sharpless AD reaction.
(neat) nmax 2980, 1737, 1701, 1527, 1450, 1368, 1235, 1157, 1050, 753.
3
2
1H NMR:
d
3.29 (d, JHH¼6.0 Hz, 2H, ArCH2), 4.76 (dd, JHH¼1.5 Hz,
3JHH¼17.0 Hz, 1H, ]CHH), 4.92 (dd, 2JHH¼1.5 Hz, 3JHH¼10.0 Hz, 1H, ]
CHH), 5.74e5.82 (m, 1H, CH2CH), 6.28 (br s, 1H, NH), 7.14e7.30 (m,
3H, ArH), 7.65 (d,1H, 3JHH¼8.0 Hz, ArH); 13C NMR: 36.4 (ArCH2),116.4
(]CH2),125.3 (ArCH),125.9 (ArCH),127.7 (ArCH),130.5 (ArCH),132.8
(ArC), 135.6 (]CH), 135.9 (ArC), 154.1 (CO); MS (ES, þve): 293 (100%,
MþH); HRMS (ES þve) calcd for C19H20N2O 292.1579, found
292.1576. The filtrate was concentrated and subjected to silica gel
chromatography (5% ethyl acetate/hexanes), yielding the protected
4. Experimental
o-allylaniline 6 (1.289 g, 88%) as a colourless oil.12 1H NMR:
d 1.51 (s,
4.1. General procedures
9H, CH3), 3.35 (d, 3JHH¼6.0 Hz, 2H, ArCH2), 5.01e5.09 (m,1H, ]CHH),
5.12e5.17 (m, 1H, ]CHH), 5.88e6.01 (m, 1H, CH2CH), 6.45 (br s, 1H,
NH), 7.00e7.06 (m, 1H, ArH), 7.11e7.14 (m, 1H, ArH), 7.19e7.25 (m,
Reagents and solvents were purchased reagent grade and used
without further purification unless otherwise stated. THF and Et2O
were distilled from sodium/benzophenone and CH2Cl2 was distilled
from CaH2. All reactions were performed in standard oven-dried
glassware under a nitrogen atmosphere unless otherwise stated.
UV irradiation was carried out with a 500 W Iwasaki Electric Lamp
at 250e400 nm. Melting points were determined using a Gallen-
kamp (Griffin) melting point apparatus. Temperatures are
expressed in degrees Celsius (ꢀC) and are uncorrected.
1H, ArH), 7.78 (d, 3JHH¼7.8 Hz, 1H, ArH); 13C NMR:
d 28.2 (CH3), 36.4
(ArCH2), 80.2 (C(CH3)3), 116.5 (]CH2), 121.9 (ArCH), 123.9 (ArCH),
127.3 (ArCH), 128.9 (ArC), 129.9 (ArCH), 135.8 (]CH), 136.4 (ArC),
153.1 (CO); MS (CI, þve): 234 (20, MþH), 233 (18), 178 (100), 133
(18); HRMS (EI, þve) calcd for C14H19NO2 233.1416, found 233.1415.
4.2.2. E-1,4-Di(2-N-tert-butoxycarbonylaniline)-2-butene 7. To a stir-
red solution of the protected o-allylaniline 6 (101 mg, 0.433 mmol) in
CH2Cl2 (12.0 mL) was added Grubbs’ II catalyst (37 mg, 0.044 mmol)
and the mixture was heated at reflux for 7 h. The solvent was re-
moved under reduced pressure and the resulting residue was sub-
jected to silica gel chromatography (7% ethyl acetate/hexanes)
affording the alkene 7 (58 mg, 61%) as a 92:8 mixture of E/Z isomers.
Subsequent recrystallization from hexanes enriched the quantity of
the E isomer to 99% (35 mg, 37%). IR (neat) nmax 3360, 1693, 1516,
Proton (1H) and carbon (13C) nuclear magnetic resonance (NMR)
spectra were recorded at 300 and 75 MHz, respectively, on a Varian
Mercury 300 MHz spectrometer in CDCl3. Alternatively, where
stated, 1H and 13C NMR spectra were recorded at 500 and 125 MHz
on a Varian Inova 500 MHz spectrometer. Chemical shifts (
reported in parts per million relative to TMS (
¼0 ppm) or CDCl3
¼77.0 ppm) as internal standards. Coupling constants (J) are
d) are
d
(d
reported in hertz (Hz). Multiplicities are reported as singlet (s),
broad singlet (br s), doublet of doublets (dd) or multiplet (m).
Chemical ionization (CI) and Electron impact (EI) mass spectra
(MS) were recorded on a Shimadzu QP-5000 spectrometer and high
resolution (HR) on a VG AutoSpec spectrometer. Electrospray (ES)
mass spectra were recorded on a Micromass Platform LCZ spec-
trometer and high resolution on a Micromass QTOF2 spectrometer.
Ion mass to charge (m/z) values are stated with their relative
abundances as a percentage in parentheses. Peaks assigned to the
molecular ion are denoted by Mþ.
1453, 1301, 1242, 1158, 1055, 744. 1H NMR (500 MHz):
d 1.50 (s, 18H,
CH3), 3.36(d, 3JHH¼2.7 Hz, 4H, CH2), 5.63e5.66 (m, 2H, ]CH), 6.54 (br
3
s, 2H, NH), 7.01e7.05 (m, 2H, ArH), 7.12 (d, JHH¼7.0 Hz, 2H, ArH),
3
7.20e7.23 (m, 2H, ArH) 7.75 (d, JHH¼6.5 Hz, 2H, ArH); 13C NMR
(125 MHz):
d 28.3 (CH3), 35.2 (CH2), 80.3 (C(CH3)3), 122.1 (ArCH),
124.1 (ArCH), 127.3 (ArCH), 129.6 (ArC), 129.7 (]CH), 129.8 (ArCH),
136.3 (ArC),153.1 (CO); MS (EI, þve): 438 (7, Mþ),132 (100); HRMS (CI
þve) calcd for C26H35N2O4 439.2597, found 439.2584.
4.2.3. Z/E Isomerization. To a stirred solution of the alkene 7 (E/Z,
46:54) (75 mg, 0.17 mmol) in benzene (5 mL) was added diphenyl
disulfide (20 mg, 0.09 mmol) and the mixture was heated at reflux
under UV irradiation for 7 h. The solution was concentrated under
reduced pressure and the residue was subjected to gravity silica
chromatography (8% ethyl acetate/hexanes) yielding the alkene 7
(E/Z, 83:17) (72 mg, 96%).
High Performance Liquid Chromatography (HPLC) was performed
using a Waters 1515 pump and a Daicel Chiralcel OD-H column with
a flow rate of 1 mL/min and a detection wavelength of 254 nm. En-
antiomeric excesses (ee) were determined by analysis of analyte peak
area. Thin Layer Chromatography (TLC) was performed using Merck
Silica Gel F254 aluminium sheets. Column chromatography was per-
formed under gravity using Merck Silica Gel 60 (0.063e0.200 mm).
Eluents are in volume to volume (v/v) proportions.
4.2.4. (2S,3S)-1,4-Di(2-N-tert-butoxycarbonylaniline)-2,3-butandiol
For all reactions performed on mixtures of stereoisomers an
overall yield is stated. Where the diastereomeric products were
separated by chromatography the yields are based on the quantity
of the relevant isomer in the starting mixture. The quantity of each
isomer in the mixtures was in all cases determined by 1H NMR
analysis. Peaks in the 1H and 13C NMR arising due to unwanted Z or
8dgeneral procedure A. A solution of ADmix a (200 mg, 0.57 mmol
Os) and methanesulfonamide (15 mg, 0.16 mmol) in water (2.5 mL)
was cooled to 0 ꢀC. To this mixture was added a solution of the E-
alkene 7 (99% geometrical purity) (60 mg, 0.14 mmol) in tert-
butylalcohol (3 mL) and the resulting slurry was stirred at 0 ꢀC in air
for 90 h. Sodium sulfite (2.2 g) was added and stirring was con-
tinued for 30 min. The reaction mixture was then extracted with
ethyl acetate (3ꢁ10 mL) and the combined organic layers were
washed with 2 M KOH (2ꢁ10 mL) and dried (MgSO4). The solution
was concentrated and subjected to silica gel chromatography
(13e30% ethyl acetate/hexanes) affording the (2S,3S)-diol 8 (22 mg,
34%) as a white solid, mp 140e145 ꢀC. IR (neat) nmax 3432, 3288,
2976, 1690, 1517, 1452, 1368, 1299, 1246, 1158, 1048, 1022, 756. 1H
meso impurities are marked with an asterix (
*
).
4.2. Synthesis of biindolinedScheme 1
4.2.1. N-tert-Butoxycarbonyl-o-allylaniline 6.12 A solution of o-allyl-
aniline 5 (845 mg, 6.34 mmol) in diethyl ether (10 mL) was cooled to
0 ꢀC. To this was added triethylamine (700 mg, 6.91 mmol) followed
by a solution of di-tert-butyldicarbonate (1.50 g, 8.61 mmol) in
diethyl ether (10 mL) and the mixture was stirred at 0 ꢀC for 10 min
and then at rt for a further 4.5 h. The mixture was diluted with
hexanes (15 mL) and the precipitate removed by suction filtration,
washed with hexanes and dried in vacuo yielding the urea N,N-
diBoc-1,3-bis(2-allylphenyl)urea (52 mg, 6%) as a white solid. FTIR
NMR:
d 1.49 (s, 18H, CH3), 2.80e2.94 (m, 4H, CH2), 3.26 (br s, 2H,
OH), 3.65e3.73 (m, 2H, CHOH), 7.03e7.25 (m, 6H, ArH), 7.62 (d,
3JHH¼7.8 Hz, 2H, ArH), 7.67 (s, 2H, NH); 13C NMR:
d 28.4 (CH3), 35.4
(CH2), 74.9 (CHOH) 80.3 (C(CH3)3), 123.9 (ArCH), 124.6 (ArCH), 127.4
(ArCH), 129.9 (ArC), 130.5 (ArCH) 137.0 (ArC), 154.2 (CO); MS (EI,
þve): 472 (12, Mþ), 106 (100); HRMS (EI, þve) calcd for C26H36N2O6

M.J. Gresser et al. / Tetrahedron 66 (2010) 6965e6976
6969
472.2573, found 472.2568. HPLC analysis (10% 2-propanol/hexane,
retention times (2R,3R)-diol 8 8.2 min (minor), (2S,3S)-diol 8
16.2 min (major)) showed the ee of the (2S,3S)-diol 8 was 50%.
component was extracted with CH2Cl2 (3ꢁ10 mL) and the combined
extracts were washed with brine (20 mL) and dried (MgSO4). The
solution was concentrated and subjected to silica gel chromatogra-
phy (3% ethyl acetate/hexanes) affording the (2S,20S)-biindole 10
(23 mg, 74%) as a white solid, mp 180e185 ꢀC. IR (neat) nmax 1696,
4.2.5. (2R,3R)-1,4-Di(2-N-tert-butoxycarbonylaniline)-2,3-butandiol
8. A solution of ADmix
b
(150 mg, 0.43
mmol Os) and meth-
1485, 1390, 1373, 1341, 1313, 1161, 1139, 1021, 752. 1H NMR:
d 1.54 (s,
2
3
anesulfonamide (10 mg, 0.11 mmol) in water (2.5 mL) was cooled to
0 ꢀC. To this mixture was added a solution of the E-alkene 7 (99%
geometrical purity) (45 mg, 0.11 mmol) in tert-butylalcohol (3 mL)
and the resulting slurry was stirred at 0 ꢀC in air for 90 h. Sodium
sulfite (2.2 g) was added and stirring was continued for 30 min. The
reaction mixture was then extracted with ethyl acetate (3ꢁ10 mL)
and the combined organic layers were washed with 2 M KOH
(2ꢁ10 mL) and dried (MgSO4). The solution was concentrated and
subjected to silica gel chromatography (13e30% ethyl acetate/
hexanes) yielding the (2R,3R)-diol 8 (15 mg, 31%) with physical and
spectral properties identical to the (2S,3S)-diol 8. HPLC analysis
(10% 2-propanol/hexane, retention times (2R,3R)-diol 8 8.3 min
(major), (2S,3S)-diol 8 17.8 min (minor)) showed the ee of the
(2R,3R)-diol 8 was 56%.
18H, CH3), 2.72 (dd, JHH¼16.8 Hz, JHH¼2.4 Hz, 2H, CHH), 3.16 (dd,
2JHH¼16.8 Hz, JHH¼9.6 Hz, 2H, CHH), 4.96e5.01 (m, 2H, CHN),
3
6.87e6.93 (m, 2H, ArH), 7.01 (d, 3JHH¼7.2 Hz, 2H, ArH), 7.13e7.20 (m,
2H, ArH), 7.70 (br s, 2H, ArH); 13C NMR:
d 28.4 (CH3), 29.7 (CH2), 60.0
(CHN), 81.3 (C(CH3)3), 115.5 (ArC), 122.5 (ArCH), 124.5 (ArCH), 127.3
(ArCH), 129.7 (ArCH), 143.3 (ArC), 152.6 (CO); MS (EI, þve): 436 (17,
Mþ), 118 (100); HRMS calcd for C26H32N2O4 436.2362, found
436.2345. HPLC analysis (2.5% 2-propanol/hexane, retention times
(2S,20S)-biindoline 10 13.0 min (major), (2R,20R)-biindoline 10
14.8 min (minor)), showed the ee of the (2S,20S)-biindoline 10 was
69%. Further elution gave the meso-biindoline 10 (5 mg, 64%) as
a white solid. 1H NMR:
d
1.48 (s, 18H, CH3), 2.67 (d, 2JHH¼16.5 Hz, 2H,
CHH), 3.23 (dd, 2JHH¼16.5 Hz, 3JHH¼10.0 Hz, 2H, CHH), 4.80e4.85 (m,
3
2H, CHN), 6.88e6.92 (m, 2H, ArH), 7.02 (d, JHH¼7.5 Hz, 2H, ArH),
7.09e7.13 (m, 2H, ArH), 7.46 (br s, 2H, ArH); 13C NMR:
d 28.3 (CH3),
4.2.6. (2S,3S)-1,4-Di(2-N-tert-butoxycarbonylaniline)-2,3-dimetha-
nesulfonylbutane 9. To a solution of the diol 8 ((2S,3S)/meso, 64:36)
(80 mg, 0.17 mmol) in CH2Cl2 (5 mL) at 0 ꢀC were added triethyl-
amine (144 mg, 1.42 mmol) and methanesulfonyl chloride (102 mg,
0.89 mmol) and the mixture was stirred at rt for 20 min. The re-
action mixture was diluted with CH2Cl2 (10 mL) and washed with
CuSO4 (15 mL), followed by satd NaHCO3 (15 mL) and brine (15 mL).
The organic component was dried (MgSO4) and the solvent re-
moved under reduced pressure yielding the dimesylate 9 (104 mg,
98%) as a white solid, and as a 64:36 mixture of the (2S,3S)/meso
diastereomers. Chromatography on gravity silica gel (20% ethyl
acetate/hexanes) afforded the (2S,3S)-dimesylate 9 (30 mg, 44%).
30.4 (CH2), 62.2 (CHN), 81.0 (C(CH3)3),115.6 (ArC),122.4 (ArCH),124.1
(ArCH), 127.1 (ArCH), 130.7 (ArCH), 143.0 (ArC), 152.7 (CO).
4.2.9. (2R,20R)-N,N0-tert-Butoxycarbonylbiindoline 10, heterocycle 11
and indoline 12. To NaH (60 mg, 60% suspension,1.50 mmol) at 0 ꢀC
was slowly added a solution of the dimesylate 9 (a mixture con-
taining 228 mg, 0.363 mmol, (2S,3S)-dimesylate 9 and 60 mg,
0.096 mmol, meso-dimesylate 9) in THF (8 mL) and the mixture was
brought to rt and stirred for 24 h. The mixturewas cooled to 0 ꢀC and
ethanol (10 mL) was slowly added, followed by water (10 mL), and
stirring was continued for 30 min. The organic component was
extracted with CH2Cl2 (3ꢁ10 mL) and the combined extracts were
washed with brine (20 mL) and dried (MgSO4). The solution was
concentrated and subjected to silica gel chromatography (3% ethyl
acetate/hexanes) affording the (2R,20R)-biindoline 10 (75 mg, 47%)
with identical physical and spectral properties to the (2S,20S)-biin-
doline 10. HPLC analysis (2.5% 2-propanol/hexane, retention times
(2S,20S)-biindoline 10 12.6 min (minor), (2R,20R)-biindoline 10
14.3 min (major)), showed the enantiomeric excess of the (2R,20R)-
biindoline 10 was 55%. Further elution gave the meso-biindoline 10
(14 mg, 33%) followed by a 50:50 mixture (2 mg) of the meso-biin-
FTIR
n
3431 (w), 3288 (w), 1690 (s), 1517 (m), 1452 (m), 1367 (s),
1.51 (s, 18H, CH3),
1298 (m), 1157 (s), 1047 (m), 756 (s). 1H NMR:
d
2
3
2.43 (s, 6H, SCH3), 3.06 (dd, JHH¼14.7 Hz, JHH¼9.6 Hz, 2H, CHH),
2
3
3.21 (dd, JHH¼14.7 Hz, JHH¼3.6 Hz, 2H, CHH), 4.97e5.03 (m, 2H,
OCH), 6.54 (s, 2H, NH), 7.10e7.16 (m, 2H, ArH), 7.25e7.32 (m, 4H,
ArH), 7.63 (d, JHH¼7.8 Hz, 2H, ArH); 13C NMR:
d 28.2 (CCH3) 31.6
3
(CH2), 37.2 (SCH3), 80.8 (OCH) 80.9 (C(CH3)3), 125.0 (ArCH), 125.2
(ArCH), 127.9 (ArC), 128.5 (ArCH), 131.4 (ArCH) 136.6 (ArC), 153.8
(CO); MS (EI, þve): 628 (4, Mþ), 118 (100); HRMS (CI, þve) calcd for
C28H41N2O10S2 629.2203, found 629.2186. Further elution gave the
dimesylate 9 (71 mg) as a 50:50 mixture of the diastereomers.
doline 10 and an unknown compound (<1%). 1H NMR (excluding
2
meso-biindoline 10):
d
1.51 (s, 18H, CH3), 2.88 (dd, JHH¼15.9 Hz,
3JHH¼2.4 Hz, 2H, CHH), 3.51 (dd, JHH¼15.9 Hz, JHH¼9.9 Hz, 2H,
2
3
4.2.7. (2R,3R)-1,4-Di(2-N-tert-butoxycarbonylaniline)-2,3-dimetha-
nesulfonylbutane 9. To a solution of the diol 8 ((2R,3R)/meso, 72:28)
(500 mg, 1.06 mmol) in CH2Cl2 (12 mL) at 0 ꢀC was added trie-
thylamine (756 mg, 7.49 mmol) and methanesulfonyl chloride
(668 mg, 5.85 mmol) and the mixture was stirred at rt for 20 min.
The reaction mixture was diluted with CH2Cl2 (10 mL) and washed
with CuSO4 (15 mL), followed by satd NaHCO3 (15 mL) and brine
(15 mL). The organic component was dried (MgSO4) and the solvent
CHH), 5.03e5.10 (m, 2H, CHN), 6.01 (dd, 2JHH¼16.5 Hz, 3JHH¼7.2 Hz,
3
2H, ArH), 6.62 (d, JHH¼15.6 Hz, 2H, ArH), 7.13e7.20 (m, 2H, ArH),
7.81 (d, 3JHH¼8.1 Hz, 2H, ArH). Increasing the gradient to 15% ethyl
acetate/hexane lead to elution of the indoline 11 (39 mg, 20%) as
a white solid. 1H NMR (500 MHz):
d 1.53 (s, 18H, CH3), 2.47 (s, 3H,
2
3
SCH3), 3.03 (dd, JHH¼14.0 Hz, JHH¼8.5 Hz, 1H, OCCHH), 3.14 (dd,
2JHH¼14.0 Hz, 3JHH¼6.0 Hz, 1H, OCCHH), 3.19e3.25 (m, 1H, NCCHH),
3
3.30e3.37 (m, 1H, NCCHH), 4.52 (d, JHH¼9.0 Hz, 1H, NCH),
removed under reduced pressure yielding the dimesylate
9
5.20e5.30 (m, 1H, OCH), 6.81 (s, 1H, NH), 6.94e6.97 (m, 1H, ArH),
7.07e7.10 (m, 1H, ArH), 7.12e7.19 (m, 3H, ArH), 7.25e7.29 (m, 1H,
(612 mg, 92%) as a 74:26 mixture of the (2S,3S)/meso diastereomers.
ArH), 7.70e7.85 (m, 2H, ArH); 13C NMR (125 MHz):
d 28.1 (NCCH2),
4.2.8. (2S,20S)-N,N0-tert-Butoxycarbonylbiindoline 10 and meso-
(2,20)-N,N0-tert-butoxycarbonylbiindoline 10. To NaH (26 mg, 60%
suspension, 0.65 mmol) at 0 ꢀC was slowly added a solution of the
dimesylate 9 (a mixture containing 45 mg, 0.072 mmol, (2R,3R)-
dimesylate 9 and 11 mg, 0.018 mmol, meso-dimesylate 9) in THF
(8 mL) and the mixture was brought to rt and stirred for 18 h. NaH
(20 mg, 60% suspension, 0.50 mmol) was again added and the
mixture was stirred for a further 24 h. The mixture was cooled to
0 ꢀC and ethanol (10 mL) was slowly added, followed by water
(10 mL), and stirring was continued for 30 min. The organic
28.3 (CH3), 34.7 (OCCH2), 37.4 (SCH3), 59.9 (NCH), 80.5 (NHCOOC
(CH3)3), 81.9 (NCOOC(CH3)3), 82.6 (OCH), 109.7 (ArC), 114.7 (ArCH),
122.9 (ArCH),124.4 (ArCH),124.5 (ArCH),127.5 (ArCH),128.4 (ArCH),
129.6 (ArC), 129.6 (ArCH), 130.8 (ArCH), 136.8 (ArC), 142.5 (ArC),
153.5 (CO); MS (EI, þve): 532 (22, Mþ), 118 (100); HRMS (EI, þve)
calcd for C27H36N2O7S 532.2243, found 532.2249.
4.2.10. (2S,20S)-Biindoline 4. A solution of the (2S,20S)-biindoline 10
(120 mg, 0.28 mmol) in CH2Cl2 (3 mL) was cooled to 0 ꢀC. To this
was slowly added TFA (310 mg, 2.73 mmol) and the mixture was

6970
M.J. Gresser et al. / Tetrahedron 66 (2010) 6965e6976
stirred at rt for 12 h. A further aliquot of TFA (103 mg, 0.91 mmol)
was added and stirring continued for an additional 4 h. The mixture
was diluted with CH2Cl2 (10 mL) and 2 M NaOH (10 mL) was added.
The organic layer was extracted with CH2Cl2 (3ꢁ10 mL) and the
combined extracts were washed with brine (20 mL) and dried
(MgSO4). The solution was concentrated and the crude residue
subjected to silica gel chromatography (ethyl acetate/hexanes/NEt3,
12:87:1) yielding (2S,20S)-biindoline 4 (53 mg, 82%) as a white solid,
yield the crude 4-methoxybenzyl bromide. A suspension of NaH
(60% dispersion in oil, 66 mg, 1.65 mmol, washed with hexanes
(ꢁ1), Et2O (ꢁ3)) in dry THF (5 mL) was cooled to 0 ꢀC and treated
with 2-allylphenol (0.20 mL, 1.5 mmol). After stirring for 50 min at
0 ꢀC, the crude 4-methoxybenzyl bromide was slowly added as
a solution in THF (2 mL), and the mixture was allowed to warm to
rt. The reaction mixture was quenched after 23 h with glacial
acetic acid (2 mL), followed by water (20 mL). The aqueous layer
was extracted with EtOAc (3ꢁ20 mL). The combined organic
layers were washed with satd NaHCO3 (3ꢁ20 mL) and dried
(MgSO4). The crude mixture was subjected to flash silica gel col-
umn chromatography (hexanes to 1% EtOAc/hexanes) to yield the
protected allylic phenol 17 (344 mg, 90%) as a colourless oil.13 1H
mp 145e148 ꢀC. FTIR
n 3360 (w), 2843 (w), 1603 (m),1481 (m),1460
2
(m), 1238 (s), 1066 (m), 745 (s). 1H NMR:
d
2.75 (dd, JHH¼15.5 Hz,
3JHH¼7.0 Hz, 2H, CHH), 3.21 (dd, JHH¼15.5 Hz, JHH¼8.0 Hz, 2H,
2
3
CHH), 3.89e3.94 (m, 2H, CHN), 4.20 (br s, 2H, NH), 6.63 (d,
3JHH¼7.5 Hz, 2H, ArH), 6.70e6.74 (m, 2H, ArH), 7.01e7.05 (m, 2H,
3
ArH), 7.09 (d, JHH¼7.0 Hz, 2H, ArH); 13C NMR:
d
33.4 (CH2), 64.9
NMR (300 MHz)
d
3.42 (d, 2H, 3JHH¼6.7 Hz, CH2CH]CH2), 3.81 (s,
(NCH), 109.5 (ArCH), 119.0 (ArCH), 124.7 (ArCH), 127.4 (ArCH), 128.6
(ArC), 150.7 (ArC); MS (EI, þve): 236 (5, Mþ), 118 (100); HRMS (E.I
þve) calcd for C16H16N2 236.1313, found 236.1310.
3H, OCH33), 5.00 (s, 2H, PhCH2), 5.01e5.08 (m, 2H, CH]CH2), 6.00
3
(tdd, 1H, JHH¼16.9, 3JHH¼10.2, JHH¼6.7 Hz, CH]CH2), 6.88e6.92
3
(m, 4H, ArH), 7.15e7.20 (m, 2H, ArH), 7.35 (d, 2H, JHH¼8.8 Hz,
ArH30); 13C NMR (75 MHz)
d 34.4 (CH2CH]CH2), 55.3 (OCH3), 69.7
4.2.11. (2R,20R)-Biindoline 4. A solution of the (2R,20R)-biindoline
10 (74 mg, 0.17 mmol) in CH2Cl2 (3 mL) was cooled to 0 ꢀC. To this
was slowly added TFA (192 mg, 1.69 mmol) and the mixture was
stirred at rt for 24 h. A further aliquot of TFA (103 mg, 0.91 mmol)
was added and stirring continued for an additional 24 h. The mix-
ture was diluted with CH2Cl2 (10 mL) and 2 M NaOH (10 mL) was
added. The organic layer was extracted with CH2Cl2 (3ꢁ10 mL) and
the combined extracts were washed with brine (20 mL) and dried
(MgSO4). The solution was concentrated and the crude residue
subjected to silica gel chromatography (ethyl acetate/hexanes/NEt3,
12:87:1) yielding (2R,20R)-biindoline 4 (25 mg, 62%) with identical
physical and spectral properties to (2S,20S)-biindoline 4.
(PhCH2), 111.8 (ArC6), 113.9 (ArC20), 115.4 (CH]CH2), 120.7 (ArC4),
127.2 (ArC5), 128.8 (ArC30), 129.0 (ArC40), 129.4 (ArC2), 129.8
(ArC3), 137.0 (CH]CH2), 156.4 (ArC1), 159.3 (ArC10); MS (EI, þve)
m/z 254 (4, Mþ), 121 (100); HRMS (EI, þve) calcd for C17H18O2
254.1307, found 254.1307.
4.3.3. 2-Allylphenyl acetate 18.14,15 Acetic anhydride (5 mL) was
added to a stirred solution of 2-allylphenol (200 mg, 0.49 mmol) in
Et3N (5 mL) at rt for 25 h. The reaction was quenched with water
and extracted with CH2Cl2 (4ꢁ20 mL). The combined organic layers
were washed with sodium hydroxide (3ꢁ20 mL) and concentrated
in vacuo. The crude product was subjected to gravity silica gel
column chromatography (5% EtOAc/hexanes) to afford the acety-
lated phenol 18 (262 mg, 99%) as a colourless, volatile liquid.z 1H
3
4.3. Synthesis of allyl monomers
NMR (300 MHz)
d
2.30 (s, 3H, CH3), 3.30 (d, 2H, JHH¼6.6 Hz,
CH2CH]CH2), 5.04e5.07 (m, 1H, CH]CHH), 5.09e5.10 (m, 1H,
CH]CHH), 5.84e5.98 (m, 1H, CH]CH2), 7.02e7.05 (m, 1H, ArH),
4.3.1. 2-Allyl-1-benzyloxybenzene 14.12 2-Allylphenol 13 (1.74 mL,
13.41 mmol) was added dropwise to a stirred suspension of NaH
(645 mg, 60% dispersion in oil, 16.11 mmol) in THF (45 mL) at 0 ꢀC.
Benzyl bromide (1.59 mL, 13.41 mmol) was added after 1 h, the
reaction was allowed to warm to rt and stirring was continued for
20 h. The reaction was quenched with isopropyl alcohol and water,
and extracted with EtOAc (3ꢁ50 mL). The combined organic layers
were washed with NaOH (2 M) and water then dried (MgSO4). The
crude oil was subjected to gravity silica gel column chromatogra-
phy (1% EtOAc/hexanes) to afford the protected phenol 14 (2.85 mg,
7.16e7.28 (m, 3H, ArH); 13C NMR (75 MHz)
d 20.9 (CH3), 34.6
(CH2CH]CH2), 116.2 (CH]CH2), 122.3 (ArC6), 126.2 (ArC4), 127.4
(ArC5), 130.4 (ArC3), 131.9 (ArC2), 135.9 (CH]CH2), 148.9 (ArC1),
169.3 (C]O); FTIR n 1760 (s),1639 (w),1488 (w), 1453 (w), 1370 (w),
1202 (s), 1170 (s), 1118 (w), 1010 (w), 915 (w), 751 (w); MS (EI, þve)
m/z 176 (20, Mþ), 147 (33), 134 (100%), 133 (67), 132 (21), 131 (79),
119 (53); HRMS (EI, þve) calcd for C11H12O2 176.0837, found
176.0837.
95%) as a volatile, colourless oil.y 1H NMR (300 MHz)
d 3.45 (d, 2H,
4.3.4. 2-Allyl-1-trifluoromethanesulfonylbenzene 19.16 2-Allylphe-
nol (1.00 g, 7.46 mmol) was added to a stirred mixture of
N-phenyltriflimide (3.4 g, 11.18 mmol) and K2CO3 (2.06 g,
14.9 mmol) in THF (50 mL). The reaction mixture was heated at
reflux and after 48 h was partitioned between CH2Cl2 and satd
NaCl. The aqueous layer was extracted with CH2Cl2 (3ꢁ20 mL)
and the combined organic layers were washed with brine
(2ꢁ20 mL), dried (MgSO4) and concentrated under reduced
pressure. The crude product was subjected to gravity silica gel
column chromatography (1% EtOAc/hexanes) to afford the tri-
flated phenol 19 (1.648 g, 83%) as a colourless, volatile liquid.16 1H
3JHH¼6.6 Hz, CH2CH]CH2), 5.02e5.09 (m, 2H, CH]CH2), 5.07 (s,
3
2H, PhCH2), 6.02 (ddt, 1H, JHH¼6.7, 10.1, 16.8 Hz, CH]CH2),
6.89e6.94 (m, 2H, ArH4 and ArH6), 7.14e7.21 (m, 2H, ArH3 and
ArH5), 7.28e7.44 (m, 5H, 5ꢁArH0); 13C NMR (75 MHz)
d 34.4
(CH2CH]CH2), 69.9 (PhCH2), 111.7 (ArC6), 115.4 (CH]CH2), 120.8
(ArC4), 127.1 (ArC20), 127.3 (ArC5), 127.7 (ArC40), 128.5 (ArC30), 129.0
(ArC2), 129.9 (ArC3), 137.0 (CH]CH2), 137.4 (ArC10), 156.3 (ArC1);
FTIR
n 1600 (w), 1492 (m), 1452 (m), 1240 (s), 1126 (w), 1024 (w),
913 (w), 750 (s), 735 (s); MS (CI, þve) m/z 225 (100%, MþH), 147
(33), 131 (43); HRMS (EI, þve) calcd for C16H16O 224.1201, found
224.1192.
2
3
NMR (300 MHz)
d
3.40 (dd, 1H, JHH¼1.4, JHH¼1.4 Hz, CHHCH]
2 3
CH2), 3.42 (dd, 1H, JHH¼1.4, JHH¼1.4 Hz, CHHCH]CH2), 5.06
4.3.2. 1-(4-Methoxybenzyloxy)-2-allylbenzene 17.13 4-Methoxy-
benzyl alcohol (0.28 mL, 2.26 mmol) was dissolved in HBr (0.6 mL,
45% solution in glacial acetic acid) and stirred for 30 min at rt. The
mixture was diluted with Et2O (20 mL) and washed with satd
NaHCO3 (4ꢁ20 mL), followed by satd NaCl (3ꢁ25 mL). The organic
layer was dried (MgSO4), filtered and concentrated in vacuo to
4
2
3
(ddd, 1H, JHH¼1.4, JHH¼2.9, JHH¼17.0 Hz, CH]CHH), 5.08 (ddd,
4
2
3
1H, JHH¼1.4, JHH¼2.8, JHH¼10.2 Hz, CH]CHH), 5.85 (ddt, 1H,
3JHH¼6.0, 10.2, 16.8 Hz, CH]CH2), 7.26e7.33 (m, 4H, ArH); 13C
NMR (75 MHz)
d 34.0 (CH2CH]CH2), 112.2, 116.5, 120.7, 125.0
(118.6, q, J¼320 Hz, CF3), 117.5 (CH]CH2), 121.3 (ArC6), 128.1
y
z
No physical or spectral data reported in Ref. 12.
No physical or spectral data reported in Refs. 14,15.

M.J. Gresser et al. / Tetrahedron 66 (2010) 6965e6976
6971
(ArC4), 128.4 (ArC5), 131.4 (ArC3), 132.8 (ArC2), 134.6 (CH]CH2),
(s), 1586 (w), 1535 (m), 1450 (w), 1370 (w), 1298 (w), 917 (w), 753
(s), 716 (w); MS (ES, þve) m/z 239 (5, MþK), 176 (3, MþH), 146 (80),
105 (100%); HRMS (ES, þve) calcd for C11H14NO 176.1075, found
176.1072.
147.9 (ArC1); FTIR
n 1483 (w), 1420 (m), 1250 (w), 1210 (s), 1138
(s), 1073 (w), 889 (s), 766 (m); MS (EI, þve) m/z 266 (9, Mþ), 265
(59), 131 (99), 115 (100%), 103 (63); HRMS (EI, þve) calcd for
C10H9F3OS 266.0225, found 266.0225.
4.3.8. 1-Allyl-2-nitrobenzene 22.22 1-Iodo-2-nitrobenzene (776 mg,
3.11 mmol) was dissolved in THF (5 mL) in a 25 mL flask flushed
with Ar(g) and fitted with a rubber septum. The flask was placed
4.3.5. 1-tert-Butyldimethylsilyloxy-2-allylbenzene 20.17 2-Allylphe-
nol (0.20 mL, 3.0 mmol) was added to a stirred suspension of
imidazole (246 mg, 3.6 mmol) in CH2Cl2 (10 mL). tert-Butyldime-
thylsilyl chloride (520 mg, 3.45 mmol) was added as a solid
and stirring was continued at rt for 18 h. The reaction mixture was
partitioned between CH2Cl2 and water, and the aqueous layer
was extracted with CH2Cl2 (3ꢁ25 mL). The organic layers were
combined and washed with water, dried (MgSO4) and the solvent
was removed under reduced pressure. The crude mixture was
subjected to a flash silica gel plug (100% hexanes) to afford the TBS
protected phenol 20 (740 mg, 99%) as a colourless, volatile liquid.17
in
a
slush bath of acetonitrile and N2(l) (ꢂ40 ꢀC). Phenyl-
magnesium bromide (3.44 mL, 1.0 M solution in THF) was added
dropwise and stirring continued a further 10 min. A solution of
copper (I) cyanide (276 mg, 3.11 mmol) and lithium chloride
(264 mg, 6.22 mmol) in THF (2 mL) was added and stirring was
continued for a further 10 min. Allyl bromide (0.32 mL, 3.42 mmol)
was then added neat and after 2 h the reaction was quenched with
satd NH4Cl, partitioned between water and Et2O and extracted
with Et2O (3ꢁ50 mL). The organic layers were combined and
washed with satd NaCl (4ꢁ30 mL), and filtered after addition of
charcoal. The filtered solution was dried (MgSO4) and the crude
residue was subjected to flash silica gel column chromatography
(hexanes) to afford the allylated product 22 (415 mg, 82%) as
1H NMR (500 MHz)
d 0.24 (s, 6H, Si(CH3)2), 1.02 (s, 9H, C(CH3)3),
3.37 (d, 2H, J¼6.5 Hz, CH2CH]CH2), 4.99e5.03 (m, 1H, CH]CHH),
5.05e5.06 (m, 1H, CH]CHH), 5.90e6.04 (m, 1H, CH]CH2), 6.79 (d,
1H, J¼8 Hz, ArH6), 6.89 (t, 1H, J¼7.4 Hz, ArH4), 7.08 (t, 1H, J¼7.7 Hz,
ArH5), 7.14 (d, 1H, J¼7.5 Hz, ArH3); 13C NMR (75 MHz)
d
ꢂ4.1 (Si
a colourless oil.22 1H NMR (300 MHz)
d
3.72 (dt, 2H, J¼1.4, 6.3 Hz,
4
2 3
(CH3)2), 18.3 (C(CH3)3), 25.8 (C(CH3)3), 34.4 (CH2CH]CH2), 115.4
(CH]CH2), 118.4 (ArC6), 121.1 (ArC4), 127.0 (ArC5), 130.1 (ArC3),
130.7 (ArC2), 137.0 (CH]CH2), 153.3 (ArC1); MS (EI, þve) m/z 247
(39, MꢂH), 237 (42), 221 (47), 205 (55), 193 (63), 179 (100%), 161
(71), 131 (92), 121 (92), 115 (79); HRMS (EI, þve) calcd for C15H23OSi
247.1518, found 247.1516.
CH2CH]CH2), 5.11 (ddd, 1H, JHH¼1.6, JHH¼2.8, JHH¼16.8 Hz,
4
2
3
CH]CHH), 5.15 (ddd, 1H, JHH¼1.4, JHH¼2.9, JHH¼10.2 Hz, CH]
3
CHH), 6.01 (ddt, 1H, JHH¼6.4, 10.2, 16.7 Hz, CH]CH2), 7.37e7.43
(m, 2H, ArH3 and 5), 7.57 (dt, 1H, J¼1.4, 7.6 Hz, ArH4), 7.94 (dd, 1H,
J¼1.4, 8.5 Hz, ArH6); 13C NMR (75 MHz)
d 36.9 (CH2), 117.1 (CH]
CH2), 124.6 (ArC6), 127.3 (ArC5), 131.9 (ArC3), 133.0 (ArC4), 134.8
(ArC2), 135.0 (CH]CH2), 150.0 (ArC1); MS (ES, þve) m/z 186 (5,
MþNa), 146 (5), 135 (10), 121 (5), 94 (18), 83 (100%).
4.3.6. 2-Allyl-1-methoxybenzene 23.18 2-Allylphenol (507 mg,
3.73 mmol) was dissolved in acetone (40 mL) and K2CO3 (2.063 g,
14.9 mmol) was added, followed by a few drops of water. The re-
action vessel was heated to 40 ꢀC and methyl iodide (0.94 mL,
14.9 mmol) was added. After 20 h the solvent was removed under
reduced pressure, the crude mixture dissolved in EtOAc and
washed with water (3ꢁ30 mL). The organic layer was dried
(MgSO4) and adsorbed onto silica gel. After flash silica gel column
chromatography (hexanes), the protected allylphenol 23 (482 mg,
87%) was obtained as a colourless, volatile liquid.18 1H NMR
4.3.9. 3-Allyl-1-methoxybenzene 24.28 Magnesium turnings (292 mg,
12.0 mmol) were washed sequentially with 1 M HCl, EtOH and Et2O
and placed in an oven-dried flask. The flask and magnesium were
then flame-dried under a N2(g) purge. THF (10 mL) was added and 3-
bromoanisole (0.27 mL, 2.13 mmol) was slowly added. One crystal of
iodine was added, and the reaction vessel was warmed in an oil bath
(25 ꢀC). The remaining 3-bromoanisole (1.0 mL, 7.87 mmol) was
slowly added in four portions, over 1 h. The reaction was stirred for
a further 1 h; some residual magnesium remained, and a grey pre-
cipitate was observed. Allyl bromide (1.7 mL, 20.0 mmol) was slowly
added, and stirring was continued at 25 ꢀC for 20 h. The mixture was
partitioned between Et2O and satd NH4Cl. The aqueous layer was
extracted with a Et2O (3ꢁ25 mL), the combined organic layers dried
(MgSO4)and thesolventwasevaporated underreduced pressure. The
crude oil was subjected to flash silica gel column chromatography
(hexanes) to afford the protected phenol 24 (855 mg, 58%) as a col-
(500 MHz)
d
3.38 (d, 2H, J¼6.2 Hz, CH2), 3.81 (s, 3H, OCH3),
5.02e5.06 (m, 2H, CH]CH2), 5.95e6.03 (m, 1H, CH]CH2), 6.84 (d,
1H, J¼8.1 Hz, ArH6), 6.89 (t, 1H, J¼7.4 Hz, ArH4), 7.13 (d, 1H,
J¼7.3 Hz, ArH3), 7.19 (t, 1H, J¼7.7 Hz, ArH5); 13C NMR (125 MHz)
d
34.2 (CH2), 55.3 (OCH3), 110.3 (ArC6), 115.3 (CH]CH2), 120.5
(ArC4), 127.3 (ArC5), 128.6 (ArC2), 129.7 (ArC3), 137.0 (CH]CH2),
157.3 (ArC1); FTIR n 1600 (w),1493 (m),1464 (w),1243 (s),1050 (w),
1031 (m), 912 (w), 751 (s); MS (EI, þve) m/z 148 (17, Mþ), 147 (90,
MꢂH), 131 (100%), 121 (78), 105 (55); HRMS (EI, þve) calcd for
C10H12O 148.0888, found 148.0888.
ourless oil.28 1H NMR (500 MHz)
d
3.35 (d, 2H, J¼6.6 Hz, CH2), 3.77 (s,
3H, OCH3), 5.05e5.10 (m, 2H, CH]CH2), 5.95 (tdd, 1H, J¼6.7, 9.9,
13.5 Hz, CH]CH2), 6.73e6.75 (m, 2H, ArH2 and ArH6), 6.77 (d, 1H,
J¼7.5 Hz, ArH4), 7.19 (t, 1H, J¼8.2 Hz, ArH5); 13C NMR (125 MHz)
4.3.7. N-Acetyl-2-allylaniline 21.21 Acetic anhydride (5 mL) was
added to a stirred solution of 2-allylaniline 5 (153 mg, 1.149 mmol)
in Et3N (0.4 mL) at rt. The reaction was quenched after 3 days with
water and extracted with CH2Cl2 (4ꢁ20 mL). The combined organic
layers were washed with 2 M NaOH (3ꢁ20 mL) and concentrated in
vacuo. The crude product was subjected to gravity silica gel column
chromatography (20e40% EtOAc/hexanes) to afford the acetylated
aniline 18 (128 mg, 65%) as a white solid, mp 90e91 ꢀC (lit.21
d
40.2 (CH2), 55.0 (OCH3),111.4 (ArC6),114.2 (ArC2), 115.8 (CH]CH2),
120.9 (ArC4), 129.3 (ArC5), 137.2 (CH]CH2), 141.6 (ArC3), 159.7
(ArC1); FTIR 1600 (m),1585 (m),1489 (m),1455 (w),1436 (w),1259
n
(s), 1162 (w), 1149 (m), 1049 (m), 914 (m), 877 (w), 778 (m), 748 (m);
MS(EI, þve) m/z148 (12, Mþ),147 (20, MꢂH),131 (59),120(100%),109
(83); HRMS (EI, þve) calcd for C10H12O 148.0888, found 148.0890.
95e96 ꢀC) 1H NMR (300 MHz)
d
1.81 (br s, 1H, NH), 2.07 (CH3),
4.4. Synthesis of olefin by metathesis
2
3
3.30 (dt, 2H, JHH¼1.4, JHH¼6.1 Hz, CH2CH]CH2), 5.02 (dd, 1H,
2JHH¼1.3 Hz, 3JHH¼17.2 Hz, CH2CH]CHH), 5.10 (dd, 1H, 2JHH¼1.0 Hz,
4.4.1. E-1,4-Di(2-benzyloxy)phenyl-2-butene 15. Grubbs’ I catalyst
(195 mg, 0.237 mmol, 6.7 mol %) was added to a solution of alkene
14 (820 mg, 3.68 mmol) in CH2Cl2 (20 mL) and the solution was
heated at reflux for 4.5 h. The reaction mixture was concentrated in
vacuo and subjected to gravity silica column chromatography (1%
EtOAc/hexanes) yielding the dimer 15 (629 mg, 81%, E/Z 5.2:1) as
3JHH¼10.0 Hz, CH2CH]CHH), 5.90 (ddt, 1H, JHH¼6.1, 10.3, 16.4 Hz,
3
CH]CH2), 7.04e7.21 (m, 3H, ArH), 7.74 (d, 1H, J¼8.0 Hz, ArC6); 13
C
NMR (75 MHz)
d 24.2 (CH3), 36.9 (CH2CH]CH2), 116.5 (CH]CH2),
123.8 (ArC6), 125.3 (ArC4), 127.4 (ArC5), 129.9 (ArC2), 130.2 (ArC3),
136.0 (ArC1), 136.3 (CH]CH2), 168.3 (C¼O); FTIR 3273 (w), 1656
n

6972
M.J. Gresser et al. / Tetrahedron 66 (2010) 6965e6976
a white solid, mp 68e70 ꢀC. 1H NMR (300 MHz)
d
3.42 (d, 4H,
131 (100%), 115 (93), 109 (67); HRMS (ES, þve) calcd for
C18H14F6O6S2 504.0136, found 504.0127.
J¼4.9 Hz, CH2), 3.54
*
(d, J¼5.1 Hz), 5.05 (s, 4H, PhCH2), 5.07
*
,
5.68e5.70 (m, 2H, CH]CH), 6.86e6.91 (m, 4H, ArH4 and ArH6),
7.12e7.17 (m, 4H, ArH3 and ArH5), 7.28e7.43 (m, 10H,10ꢁArH0); 13C
4.4.5. E-1,4-Di(2- tert-butyldimethylsilyloxy)phenyl-2-butene 32.
Grubbs’ II catalyst (34 mg, 0.040 mmol, 5 mol %) was added to
a solution of alkene 20 (200 mg, 0.805 mmol) in CH2Cl2 (8 mL) and
the solution was heated at reflux for 3 days. The reaction mixture
was adsorbed onto silica gel and subjected to flash silica gel column
chromatography (hexanes) yielding the dimer 32 as a pale yellow
semi-solid (97 mg, E/Z 12:1). Further elution yielded two more
portions of 32, with a total mass of 180 mg (95%) and a decreasing
NMR (75 MHz)
d
27.9 , 33.1 (CH2), 67.9 (PhCH2), 111.7 (ArC6), 120.8
*
(ArC4), 127.1 (ArC20), 127.2 (ArC10), 127.6 (ArC5), 128.5 (ArC30), 129.6
(ArC3), 129.8 (CH]CH), 129.9 (ArC2), 137.4 (ArC10), 156.3 (ArC1);
MS (CI, þve) m/z 421 (47, MþH), 237 (72), 147 (100%); MS (EI, þve)
420 (10, Mþ), 329 (30), 313 (10), 237 (30), 223 (40), 197 (40), 107
(100); HRMS (EI, þve) calcd for C30H28O2 420.2089, found
420.2087.
E/Z ratio (6:1 and 4:1). 1H NMR (500 MHz)
0.24 , 0.99 (s, 18H, C(CH3)3), 1.02
, 3.34 (d, 4H, J¼3.9 Hz, CH2), 3.47
d 0.20 (s, 12H, Si(CH3)2),
4.4.2. E-1,4-Di(2-(4-methoxybenzyloxy)phenyl)-2-butene 29. Grubbs’
II catalyst (34 mg, 0.039 mmol, 5 mol %) was added to a solution of
alkene 17 (180 mg, 0.708 mmol) in CH2Cl2 (6 mL) and the solution
was heated at reflux for 23 h. The reaction mixture was concen-
trated in vacuo and subjected to flash silica gel column chroma-
tography (2% EtOAc/hexanes) to yield the dimer 29 (27 mg, E/Z 3:1)
as a white solid. Further elution (2e50% EtOAc/hexanes) yielded 5
more portions of 29, with a total mass of 121 mg (71%) and an in-
creasing E/Z ratio (5:1 to 20:1). The fractions were combined and
recrystallisation from CH2Cl2/hexanes gave the pure E isomer as
a white solid (80 mg, 47%), mp 132e133 ꢀC. 1H NMR (300 MHz)
*
*
*
(d, J¼4.8 Hz, CH2), 5.61e5.62 (m, 2H, CH]CH), 5.70 (t, J¼4.6 Hz,
*
CH]CH), 6.77 (d, 2H, J¼8.1 Hz, ArH6), 6.87 (t, 2H, J¼7.4 Hz, ArH4),
7.06 (t, 2H, J¼7.6 Hz, ArH5), 7.13 (d, 2H, J¼7.4 Hz, ArH3); 13C NMR
(125 MHz)
(CH3)3), 25.82
(ArC4), 121.1 , 126.78
CH),129.7 ,130.1 (ArC3),131.5 (ArC2),153.3 (ArC1); FTIR
d
ꢂ4.2 (Si(CH3)2), -4.1
*
, 18.25 (C(CH3)3), 18.29
*
, 25.81 (C
, 121.0
(CH]CH), 129.6 (CH]
2952 (m),
*
, 27.8
*
, 33.1 (CH2), 118.34 (ArC6), 118.39
, 126.80 (ArC5), 128.7
*
*
*
*
*
n
2923 (m), 2857 (s), 1489 (s), 1448 (s), 1252 (s), 922 (s), 838 (s), 780
(s), 753 (s); MS (EI, þve) m/z 468 (8, Mþ), 411 (92), 295 (18), 281
(91), 247 (42), 221 (87), 203 (45), 179 (78), 165 (100%), 115 (92);
HRMS (EI, þve) calcd for C28H44OSi2 468.2880, found 468.2866.
d
3.39 (d, 4H, J¼4.8 Hz, CH2CH]CH2), 3.80 (s, 6H, OCH3), 4.98 (s, 4H,
PhCH2), 5.66 (m, 2H, CH]CH), 6.84e6.90 (m, 8H, ArH), 7.13e7.20
(m, 4H, ArH), 7.28e7.38 (m, 4H, ArH30); 13C NMR (75 MHz)
d
33.1
4.4.6. E-1,4-Di(2-hydroxyphenyl)-2-butene 33. Tetrabutylammo-
nium fluoride (2.6 mL,1 M solution inTHF) was added to 32 (310 mg,
0.661 mmol, E/Z 15.6:1) under N2(g) and the reaction mixture was
stirred at rt for 21 h. The solvent was removed in vacuo, and the
crude solid was dissolved in CH2Cl2 and washed with water. The
alkene 33 (21 mg, 13%, E/Z 27:1) was recrystallised from CH2Cl2/
hexanes as a white solid, mp 126e128 ꢀC. Two additional crops of 33
(123 mg, 79%) were obtained by recrystallisation from the filtrate to
(CH2), 55.3 (OCH3), 69.7 (PhCH2), 111.7 (ArC6), 113.8 (ArC20), 120.7
(ArC4), 127.0 (ArC5), 128.7 (ArC30), 129.4 (ArC40), 129.5 (CH]CH),
129.7 (ArC3), 129.8 (ArC2), 156.4 (ArC1), 159.2 (ArC10); FTIR
n 1614
(w),1587 (w), 1515 (w),1489 (w),1451 (w),1378 (w),1252 (w), 1230
(w), 1106 (w), 1032 (w), 998 (w); MS (EI, þve) m/z 480 (5, Mþ), 241
(12),121 (100%); HRMS (EI, þve) calcd for C32H32O4 480.2301, found
480.2291.
give a total yield of 92% (144 mg). 1H NMR (300 MHz, CD3OH)
d 3.30
2
3
4.4.3. E-1,4-Di(2-acetyloxyphenyl)-2-butene 30. Grubbs’ I catalyst
(61 mg, 0.074 mmol, 5 mol %) was added to a solution of alkene 18
(262 mg, 1.49 mmol) in CH2Cl2 (12 mL) and the solution was heated
at reflux for 15 h. The reaction mixture was adsorbed onto silica gel
and subjected to gravity silica gel column chromatography (5e7%
EtOAc/hexanes) to yield the dimer 30 (204 mg, 85%, E/Z 4:1) as
(dd, 4H, JHH¼1.4, JHH¼3.5 Hz, CH2CH]CH2), 4.89 (br s, 2H, OH),
5.61e5.65 (m, 2H, CH]CH), 6.70e6.75 (m, 4H, ArH), 6.95e7.05 (m,
4H, ArH); 13C NMR (75 MHz, CD3OH)
d
33.9 (CH2),115.8 (ArC6),120.6
(ArC4), 128.0 (ArC5), 128.6 (ArC2), 130.6 (CH]CH), 130.8 (ArC3),
156.0 (ArC1); FTIR 3084 (w), 2395 (w),1711 (w),1369 (w),1230 (w),
n
1073 (s); MS (ES, ꢂve) m/z 275 (23, MþCl), 239 (100%, MꢂH); HRMS
a colourless oil. 1H NMR (300 MHz)
(dd, 4H, J¼1.4, 3.7 Hz, CH2), 3.38 (d, J¼5.3 Hz, CH2), 5.56e5.59 (m,
, 7.00e7.05 (m, 2H, ArH), 7.14e7.26 (m, 6H,
20.8 (CH3), 27.9 , 33.3 (CH2), 122.3
, 127.3 (ArC5), 128.2 , 129.2 (CH]CH),
, 148.8 (ArC1), 169.3 (C¼O);
d
2.24 (s, 6H, CH3), 2.28
*
, 3.26
(ES, ꢂve) calcd for C16H15O2 239.1072, found 239.1080.
*
2H, CH]CH), 5.62e5.65
*
4.4.7. E-1,4-Di(2-N-acetylaniline)-2-butene 34. Grubbs’ II catalyst
(15 mg, 0.035 mmol, 10 mol %) was added to a solution of N-acetyl-
2-allylaniline 21 (67 mg, 0.35 mmol) in CH2Cl2 (6 mL). The mixture
was heated at reflux for 17 h then filtered to collect the metathesis
product 34 (45 mg, 73%) as a white powder, decomp. 220 ꢀC. 1H
ArH); 13C NMR (75 MHz)
(ArC6), 126.1 (ArC4), 126.2
d
*
*
*
129.9
FTIR
*
, 130.3 (ArC3), 132.3 (ArC2), 132.4
*
n
3275 (m), 1654 (s), 1533 (s), 1449 (s), 1369 (s), 1295 (s), 973
(s), 749 (s); MS (EI, þve) m/z 324 (11, Mþ), 282 (16), 264 (11), 176
(10), 147 (33), 133 (100%), 131 (68), 107 (75); HRMS (EI, þve) calcd
for C20H20O4 324.1362, found 324.1354.
NMR (300 MHz, DMSO)
d
1.99 (s, 6H, CH3), 3.31 (d, 4H, J¼4.2 Hz,
CH2), 5.50 (t, 2H, J¼3.3 Hz, CH]CH), 7.04e7.17 (m, 6H, ArH), 7.37 (d,
2H, J¼7.7 Hz, ArH6), 9.21 (br s, 2H, NH); 13C NMR (75 MHz,)
d 23.2
(CH3), 34.0 (CH2), 125.2 (ArC6), 125.7 (ArC4), 126.2 (ArC5), 129.2
4.4.4. E-1,4-Di(2-trifluoromethanesulfonylphenyl)-2-butene 31.
Grubbs’ I catalyst (23 mg, 0.028 mmol, 5 mol %) was added to
a solution of alkene 19 (151 mg, 0.568 mmol) in CH2Cl2 (6 mL) and
the solution was heated at reflux for 15 h. The reaction mixture was
adsorbed onto silica gel and subjected to gravity silica gel column
chromatography (0.5e1% EtOAc/hexanes) to afford the dimer 31
(126 mg, 88%, E/Z 3.8:1) as a colourless oil. 1H NMR (300 MHz)
(ArC3), 129.3 (ArC2), 134.2 (ArC1), 135.9 (CH]CH), 169.3 (C]O);
FTIR
n 3275 (w), 1655 (s), 1587 (w), 1534 (m), 1449 (w), 1369 (w),
1296 (s), 1272 (w), 973 (w), 849 (w), 750 (s), 706 (w); MS (ES, þve)
m/z 345 (5, MþNa), 323 (5, MþH), 146 (100%), 105 (40); HRMS (ES,
þve) calcd for C20H22N2O2Na 345.1579, found 345.1584.
4.4.8. E-1,4-Di(2-nitrophenyl)-2-butene 35. Grubbs’ II catalyst
(48 mg, 0.057 mmol, 5 mol %) was added to a solution of 2-allylni-
trobenzene 22 (185 mg, 1.14 mmol) in CH2Cl2 (5 mL), and the flask
was flushed with Ar(g) and heated at reflux for 7 h. The reaction
mixture was washed with water, and the aqueous layer was
extracted with CH2Cl2 (3ꢁ20 mL). Charcoal was added to the com-
bined organic layers and filtered. Hexane was added to the filtrate,
and a brown solid was crystallised and collected. The brown solid
was subjected to gravity silica gel column chromatography (3%
d
3.48 (dd, 4H, J¼1.5, 3.6 Hz, CH2), 3.59
(ddd, 2H, J¼1.5, 3.6, 5.1 Hz, CH]CH), 5.73
CH]CH), 7.23e7.34 (m, 8H, ArH); 13C NMR (75 MHz)
(CH2), 112.2, 116.5, 120.7, 124.9 (118.6, q, J¼320 Hz, CF3), 121.3
(ArC6), 128.1 (ArC4), 128.2 (CH]CH), 128.4 (ArC5), 128.5 , 129.3
(CH]CH), 131.0 , 131.3 (ArC3), 133.0 (ArC2), 147.9 (ArC1); FTIR
*
(dd, J¼0.9, 4.6 Hz, CH2), 5.65
(ddd, J¼0.9, 4.6, 5.5 Hz,
27.6 , 32.8
*
d
*
*
*
*
n
3350 (m), 2950 (m), 1678 (s), 1525 (s), 1167 (s), 1098 (s), 740 (s); MS
(EI, þve) m/z 504 (27, Mþ), 359 (13), 281 (33), 265 (100%), 239 (80),

M.J. Gresser et al. / Tetrahedron 66 (2010) 6965e6976
6973
EtOAc/hexanes) to yield the homo-coupled product 35 (44 mg, 26%,
E/Z 43:1) as a white solid, mp 78 ꢀC. 1H NMR (500 MHz)
3.65e3.66
(m, 4H, CH2), 3.82
, 5.70 (ddd, 2H, J¼1.5, 3.5, 5.0 Hz, CH]CH),
solvent was removed in vacuo, and the crude mixture was subjected
to flash silica gel column chromatography. Elutionwith hexanes gave
thehomo-coupledproduct39(204 mg, 89%, E/Z4.7:1)asacolourless,
d
*
7.34e7.38 (m, 4H, ArH3 and 5), 7.53 (t, 2H, J¼7.6 Hz, ArH4), 7.89 (d,
volatileoil.251HNMR(500 MHz)
d
3.36(d,4H,J¼5.1 Hz,CH2), 3.51
J¼5.5 Hz, CH2), 5.65e5.73 (m, 2H, CH]CH), 7.17e7.31 (m, 10H, ArH);
13C NMR (125 MHz)
33.5 , 38.9 (CH2CH]CH2), 125.9 (ArC4), 128.3
(ArC3), 128.4 (ArC2), 130.4 (CH]CH), 140.7 (ArC1); FTIR 3026 (w),
*
(d,
2H, J¼8.1 Hz, ArCH6); 13C NMR (125 MHz)
d 35.7 (CH2),124.6 (ArC6),
127.3 (ArC5), 129.5 (CH]CH), 131.8 (ArC3), 133.0 (ArC4), 135.1
d
*
(ArC2), 149.2 (ArC1); FTIR
n
2960 (w), 2351 (w), 2335 (s), 1518 (s),
n
1353 (s),1086 (m), 783 (s), 723 (s); MS (ES, þve) m/z 321 (28, MþNa),
299 (2, MþH), 297 (2), 146 (5), 105 (100%), 64 (40); HRMS (ES, þve)
calcd for C16H14N2O4Na 321.0851, found 321.0854.
2362 (w),1602 (w),1494 (m),1452 (w), 969 (w), 737 (w), 697 (s); MS
(EI, þve) m/z 208 (49, Mþ), 130 (48), 117 (100%), 104 (50); HRMS (EI,
þve) calcd for C16H16 208.1252, found 208.1257.
4.4.9. E-1,4-Di(2-methoxyphenyl)-2-butene 36. Grubbs’ I catalyst
(51 mg, 0.062 mmol, 5 mol %) was added to a solution of alkene 23
(183 mg, 1.236 mmol) in CH2Cl2 (10 mL) and the solution was
heated at reflux for 7 h. The reaction mixture was adsorbed onto
silica gel and subjected to flash silica gel column chromatography
(1% EtOAc/hexanes) to afford the dimer 36 (151 mg, 91%, E/Z 4.5:1)
4.4.13. E-1,4-Di-(2-tolyl)-2-butene 40.26 Grubbs’ I catalyst (31 mg,
0.038 mmol, 2.5 mol %) was added to a solution of alkene 2724
(200 mg, 1.515 mmol) in CH2Cl2 (6 mL) and the solution was heated
at reflux for 27 h. The solvent was evaporated and the crude mixture
was subjected to flash silica gel column chromatography and eluted
with hexanes to give the dimer 40 (73 mg, E/Z 6:1) as a colourless oil.
Further elution yielded a second portion of 40 (64 mg, E/Z 3:1), giving
as a colourless oil. 1H NMR (300 MHz)
3.50
(d, J¼4.9 Hz), 3.81 (s, 6H, OCH3), 5.64e5.68 (m, 2H, CH]CH),
6.83 (d, 2H, J¼8.1 Hz, ArH6), 6.88 (dt, J¼1.1, 7.4, 7.5 Hz, ArH4),
7.14e7.21 (m, 4H, ArH3 and ArH5); 13C NMR (75 MHz)
32.9 (CH2),
55.3 (OCH3), 110.2 (ArC6), 120.4 (ArC4), 123.8 (ArC2), 127.0 (ArC5),
129.5 (CH]CH), 129.6 (ArC3), 157.2 (ArC1); FTIR 2956 (w), 2833
d
3.35 (d, 4H, J¼4.2 Hz, CH2),
*
a total yield of 77%.26 1H NMR (500 MHz)
3.33 (d, 4H, J¼3.5 Hz, CH2), 3.48 , 5.56 (m, 2H, CH]CH), 5.65
7.11e7.14 (m, 8H, ArH); 13C NMR (500 MHz)
19.3 (CH3), 31.3
(CH2),125.9 (ArC4 or ArC5),126.0 ,126.1 (ArC4 or ArC5),128.5 ,128.9
, 136.2
d
2.27 (s, 6H, CH3), 2.32
*
,
*
*
,
d
d
*
, 36.4
*
*
n
(ArC3 or ArC6), 129.4 (CH]CH), 130.0 (ArC3 or ArC6), 130.1
*
(w), 1595 (m), 1493 (s), 1460 (s), 1243 (s), 1049 (s), 1027 (s), 752 (s);
MS (EI, þve) m/z 268 (25, Mþ), 147 (100%), 121 (75); HRMS (EI, þve)
calcd for C18H20O2 268.1463, found 268.1464.
(ArC2),138.8 (ArC1); MS (EI, þve) m/z 236 (7, Mþ),119 (100%); HRMS
(EI, þve) calcd for C18H20 236.1565, found 236.1565.
4.4.14. E-1,4-Di(2-bromophenyl)-2-butene 41. To a solution of 2823
(140 mg, 0.71 mmol) in DCM (5 mL) was added Grubbs’ II catalyst
(30 mg, 0.036 mmol, 5 mol %) and the reaction was heated at reflux
for 23 h. The solvent was removed in vacuo and the crude mixture
was subjected to flash silica gel column chromatography (hexanes)
to give a mixture of alkenes E-41/Z-41/E-1,4-di(2-bromophenyl)-1-
butene:E-1,5-di(2-bromophenyl)-2-pentene:E-3-(2-bromophenyl)-
1-phenylpropene:E-1-(2-bromophenyl)-3-phenylpropene (6.3:1:1.
2:1.1:1:1.2, determined by 1H NMR analysis), with a total mass of
4.4.10. E-1,4-Di(3-methoxyphenyl)-2-butene 37.29 1-Methoxy-3-
allylbenzene 24 (500 mg, 3.37 mmol) was added to a solution of
Grubbs’ I catalyst (70 mg, 2.5 mol %) in CH2Cl2 (10 mL) and the flask
was flushed with N2(g). The reaction mixture was heated at reflux
for 15 h and subjected to flash silica gel column chromatography
(1% EtOAc/hexanes) to yield the homo-coupled product 37 (283 mg,
63%, E/Z 4.5:1) as a colourless oil.x 1H NMR (500 MHz)
J¼4.3 Hz, CH2), 3.48 (d, J¼5.1 Hz, CH2), 3.76 , 3.77 (s, 6H, OCH3),
5.66e5.67 (m, 2H, CH]CH), 5.70e5.72 , 6.74 (s, 2H, ArH2),
6.72e6.81 (m, 4H, ArH4 and ArH6), 7.17e7.21 (m, 2H, ArH5); 13C
NMR (125 MHz) 33.5 , 38.9 (CH2), 55.1 (OCH3),111.3 (ArC6),113.4
114.0 , 114.1 (ArC2), 120.7 , 120.9 (ArC4), 129.0 (CH]CH), 129.3
(ArC5), 129.4
d 3.34 (d, 4H,
*
*
*
34 mg. E-41 (18 mg, 14%): 1H NMR (500 MHz)
3.4 Hz, CH2), 5.65e5.67 (m, 2H, CH]CH), 7.04e7.57 (m, 8H, ArH).
Compound Z-41 (3 mg, 2%): 1H NMR (500 MHz)
3.63 (d, 4H,
d
3.49 (dd, 4H, J¼1.6,
d
*
*
,
d
*
*
*
J¼5.3 Hz, CH2), 5.61e5.63 (m, 2H, CH]CH), 7.04e7.57 (m, 8H, ArH).
*
, 130.3 (CH]CH), 142.3 (ArC3), 159.7 (ArC1); MS (EI,
E-1,4-di(2-bromophenyl)-1-butene (3.5 mg, 3%): 1H NMR
þve) m/z 268 (58, Mþ), 147 (100%), 134 (47), 122 (57); HRMS (EI,
þve) calcd for C18H20O2 268.1463, found 268.1464.
(500 MHz) d 2.55e2.60 (m, 2H, CH]CHCH2), 2.92e2.95 (m, 2H,
CH2Ar), 6.20 (dt, 1H, J¼6.9, 6.9, 15.6 Hz, ArCH]CH), 6.74 (d, 1H,
J¼15.7 Hz, ArCH]CH), 7.04e7.57 (m, 8H, ArH). E-1,5-di(2-bromo-
4.4.11. E-1,4-Di(4-methoxyphenyl)-2-butene 38.30 4-Allyl-2-metho-
xybenzene 25 (500 mg, 3.374 mmol) was added to a solution of
Grubbs’ I catalyst (69 mg, 2.5 mol %) in CH2Cl2 (10 mL) and the flask
was flushed with Ar(g). The reaction mixturewas heated at reflux for
4.5 h and subjected to flash silica gel column chromatography (1%
EtOAc/hexanes) to yield the homo-coupled product 38 (440 mg,
97%, E/Z 6.2:1) as a white solid, mp 61e64 ꢀC (lit.30 65e66 ꢀC) 1H
phenyl)-2-pentene (3.2 mg, 2%): 1H NMR (500 MHz)
d 2.31e2.37
(m, 2H, CH2CH2Ar), 2.79e2.82 (m, 2H, CH2CH2Ar), 3.43e3.45 (m,
2H, ArCH2CH]CH), 5.55e5.58 (m, 2H, CH]CH), 7.04e7.57 (m, 8H,
ArH). E-3-(2-bromophenyl)-1-phenylpropene (3 mg, 2%): 1H NMR
(500 MHz)
d
3.71 (dd, 2H, J¼1.3, 7.0 Hz, CH2), 6.34 (dt, 1H, J¼6.7,
6.7, 15.8 Hz, CH2CH]CH), 6.45 (d, 1H, J¼15.9 Hz, CH2CH]CH),
7.04e7.57 (m, 9H, ArH). E-1-(2-bromophenyl)-3-phenylpropene
NMR (300 MHz)
OCH3), 3.682 , 5.51e5.56 (m, 2H, CH]CH), 5.57e5.59
(m, 4H, ArH2), 6.99e7.02 (m, 4H, ArH3); 13C NMR (75 MHz)
38.0 (CH2), 55.2 (OCH3), 113.8 (ArC2), 113.9 , 129.2 (CH]CH), 129.4
d
3.20e3.22 (m, 4H, CH2), 3.35e3.36
*
, 3.676 (s, 6H,
, 6.71e6.77
32.5
(3.5 mg, 3%): 1H NMR (500 MHz)
d
3.66 (dd, 2H, J¼0.9, 6.7 Hz, CH2),
*
*
6.27 (dt, 1H, J¼6.9, 6.9, 15.6 Hz, CH]CHCH2), 6.82 (d, 1H, J¼15.7 Hz,
CH]CHCH2), 7.04e7.57 (m, 9H, ArH).
d
*
,
*
*
(ArC3), 130.5 (CH]CH), 132.8 (ArC4), 157.9 (ArC1); MS (EI, þve) m/z
268 (71, Mþ),160 (62),147 (100%),134 (54),121 (86); HRMS (EI, þve)
calcd for C18H20O2 268.1463, found 268.1469.
4.5. Synthesis of diols
4.5.1. (2R,3R)-Di(2-benzyloxyphenyl)-2,3-butanediol 16. The diol
(R,R)-16b was synthesised by General procedure A using alkene 15
(80 mg, 0.19 mmol, E/Z 8.5:1), ADmix b (267 mg), meth-
anesulfonamide (18 mg, 0.19 mmol), sodium sulfite (238 mg) in
tBuOH (1.5 mL), water (1 mL) and THF (0.45 mL), for 37 h. The crude
residue was subjected to gravity silica column chromatography
(10e20% EtOAc/hexanes) to yield the chiral diol (R,R)-16 (60 mg,
69%) as a white solid, mp 57e59 ꢀC, as a mixture of chiral/meso
diastereomers (7.2:1). HPLC analysis (20e70% 2-propanol/hexane,
retention times (R,R)-diol 16 24.0 min (major), (S,S)-diol 16
4.4.12. E-1,4-Diphenyl-2-butene 39.25 Grubbs’ I catalyst (45 mg,
2.5 mol %, 0.11 mmol) was added to a solution of allylbenzene 26
(260 mg, 2.20 mmol) in CH2Cl2 (10 mL) and flushed with Ar(g). The
solutionwas heated at reflux for 18 h underan Ar(g) atmosphere. The
x
No physical or spectral data reported in Ref. 29.

6974
M.J. Gresser et al. / Tetrahedron 66 (2010) 6965e6976
33.7 min (minor)) showed the ee of the (R,R)-diol 16 was 91%. 1H
methanesulfonamide (23 mg, 0.238 mmol) and sodium sulfite
(211 mg) in BuOH (1.2 mL) and water (1.2 mL). The crude residue
2
t
NMR (300 MHz)
d
2.24 (br s, 2H, OH), 2.75 (dd, 2H, JHH¼13.5 Hz,
2
3
3JHH¼7.7 Hz, CHH), 2.87 (dd, 2H, JHH¼13.5 Hz, JHH¼5.2 Hz, CHH),
was subjected to gravity silica gel column chromatography
(10e50% EtOAc/hexanes) to yield the diol 44 (32 mg, 25%) as
a white solid, mp 110e112 ꢀC, as a mixture of chiral/meso di-
astereomers (24:1), which had identical spectral properties to the
(R,R)-44 enantiomer. HPLC analysis (20% 2-propanol/hexane, re-
tention times (R,R)-diol 44 8.76 min (minor), (S,S)-diol 44 9.42 min
(major)) showed the ee of the (S,S)-diol 44 was 1.4%.
2
3
2.99
*
(dd, JHH¼13.7 Hz, JHH¼2.4 Hz), 3.66 (dd, 2H, J¼5.7, 5.7 Hz,
* *
CHOH), 3.76
(d, J¼8.1 Hz), 4.90 (s, 4H, PhCH2), 5.98
, 6.78e6.85 (m,
4H, ArH4 and ArH6), 7.05e7.10 (m, 4H, ArH3 and ArH5), 7.23e7.29
(m, 10H, 10ꢁArH0); 13C NMR (75 MHz)
d
33.3
*
, 35.1 (CH2), 70.1
(PhCH2), 70.2
*
, 73.1 (CHOH), 74.4
*
, 111.8 (ArC6), 111.9
*
, 121.0 (ArC4),
121.1
*
, 127.2 (ArC20), 127.6 (ArC40), 127.9 (ArC5), 128.6 (ArC30), 131.5
(ArC3), 131.7
*
, 136.8 (ArC10), 156.6 (ArC1); MS (CI, þve) m/z 455
(100%, MþH), 419 (84); FTIR
n
3396 (m), 2931 (m), 2360 (m), 2331
4.5.5. (2S,2R)-1,4-Di(2-tert-butyldimethylsilyloxyphenyl)-2,3-bu-
tandiol 45 and (2R,3R)-1,4-di(2-tert-butyldimethylsilyloxyphenyl)-
2,3-butandiol 45. The diol (R,R)-45 was synthesised by General
procedure A using alkene 32 (88 mg, 0.188 mmol, E/Z 6:1), ADmix
(m), 1491 (s), 1444 (s), 1225 (s). 1045 (s), 752 (s), 728 (s); MS (ES,
þve) m/z 477 (100%, MþNa); HRMS (ES, þve) calcd for C30H30O4Na
477.2042, found 477.2044.
b
(263 mg), methanesulfonamide (18 mg, 0.188 mmol), sodium
t
4.5.2. (2S,3S)-Di(2-benzyloxyphenyl)-2,3-butanediol 16.
4.5.2.1. Procedure 1. The diol (S,S)-16 was synthesised by General
procedure A using alkene 15 (376 mg, 0.90 mmol, E/Z 3.1:1), ADmix
sulfite (166 mg) in BuOH (1 mL) and water (1 mL). The crude res-
idue was subjected to gravity silica gel column chromatography
(1e100% EtOAc/hexanes) to yield the meso diol 45 (4 mg, 4%) as
a
(1.253 g), methanesulfonamide (85 mg, 0.90 mmol), sodium sulfite
a white solid. 1H NMR (300 MHz)
d
0.25 (d, 12H, J¼3.8 Hz, Si(CH3)2),
(1.120 g) in tBuOH (4.5 mL), water (4.5 mL) and THF (1.2 mL), for 91 h.
Purification via gravity silica column chromatography (2e50%
EtOAc/hexanes) isolated the diol (S,S)-16 as a white solid (280 mg,
64%) as a mixture of chiral/meso diastereomers (15:1), mp 58e59 ꢀC,
which exhibited identical spectral properties to the (R,R)-diol. HPLC
analysis (20e70% 2-propanol/hexane, retention times (R,R)-diol 16
23.4 min (minor), (S,S)-diol 16 32.4 min (major)) showed the ee of
the (S,S)-diol 16 was 33%.
1.01 (s, 18H, C(CH3)3), 2.56 (d, 2H, J¼3.0 Hz, OH), 2.84 (dd, 2H,
2JHH¼13.7 Hz, JHH¼8.6 Hz, CHH), 3.04 (dd, 2H, JHH¼13.7 Hz,
3JHH¼2.6 Hz, CHH), 3.76e3.83 (m, 2H, CHOH), 6.83 (dd, 2H, J¼0.9,
8.0 Hz, ArH6), 6.92 (dt, 2H, J¼1.0, 7.4 Hz, ArH4), 7.11 (dt, 2H, J¼1.7,
7.8 Hz, ArH5), 7.21 (dd, 2H, J¼1.7, 7.5 Hz, ArH3); 13C NMR (75 MHz)
3
2
d
ꢂ4.1 and ꢂ4.0 (Si(CH3)2), 18.2 (C(CH3)3), 25.8 (C(CH3)3), 33.4
(CH2), 74.7 (CHOH), 118.7 (ArC6), 121.5 (ArC4), 127.5 (ArC5), 129.1
(ArC2), 131.8 (ArC3), 153.8 (ArC1); MS (ES, þve) m/z 1027 (100%,
2MþNa), 525 (25, MþNa), 503 (5%, MþH); HRMS (ES, þve) calcd for
C28H47OSi2 503.3013, found 503.3020.
4.5.2.2. Procedure 2. The diol (S,S)-16 was synthesised by
General procedure A using alkene 15 (171 mg, 0.41 mmol, E/Z
Further elution gave the chiral diol (R,R)-45 (25 mg, 27%) as
a viscous oil. HPLC analysis (2.5% 2-propanol/hexane, retention
times (R,R)-diol 45 13.3 min (major), (S,S)-diol 45 12.1 min (minor))
showed the ee of the (R,R)-diol 45 was 14%. 1H NMR (300 MHz)
3.9:1), ADmix
a (0.54 g), methanesulfonamide (39 mg, 0.41 mmol),
t
sodium sulfite (0.552 g) in BuOH (2 mL), water (2 mL), for 24 h.
Purification via gravity silica column chromatography (10e20%
EtOAc/hexanes) isolated the diol (S,S)-15 as a white solid (27 mg,
15%) as a mixture of chiral/meso diastereomers (4.8:1). HPLC
analysis (20e70% 2-propanol/hexane, retention times (R,R)-diol 15
24.3 min (minor), (S,S)-diol 15 33.0 min (major)) showed the ee of
the (S,S)-diol 15 was 64%.
d
0.20 (s, 12H, Si(CH3)2), 0.97 (s, 18H, C(CH3)3), 2.47 (d, 2H, J¼5.7 Hz,
2 3
OH), 2.82 (dd, 2H, JHH¼13.5 Hz, JHH¼5.6 Hz, CHH), 2.93 (dd, 2H,
2JHH¼13.3 Hz, JHH¼7.9 Hz, CHH), 3.67e3.73 (m, 2H, CHOH), 6.78
3
(dd, 2H, J¼1.1, 8.0 Hz, ArH6), 6.88 (dt, 2H, J¼1.2, 7.4 Hz, ArH4), 7.09
(dt, 2H, J¼1.8, 8.6 Hz, ArH5), 7.14 (d, 2H, J¼1.7, 7.4 Hz, ArH3); 13C
NMR (75 MHz)
d
ꢂ4.2 and ꢂ4.1 (Si(CH3)2), 18.2 (C(CH3)3), 25.8 (C
4.5.3. (2R,3R)-1,4-Di(2-trifluorosulfonylphenyl)-2,3-butandiol 44.
The diol (R,R)-44 was synthesised by General procedure A using
(CH3)3), 35.2 (CH2), 73.2 (CHOH), 118.6 (ArC6), 121.4 (ArC4), 127.5
(ArC5), 128.9 (ArC2), 131.6 (ArC3), 153.7 (ArC1); MS (ES, þve) m/z
1027 (100%, 2MþNa), 525 (45, MþNa), 503 (6%, MþH); HRMS (ES,
þve) calcd for C28H47OSi2 503.3013, found 503.3008.
alkene 31 (120 mg, 0.238 mmol, E/Z 9.1:1), ADmix
b (333 mg),
methanesulfonamide (23 mg, 0.238 mmol), sodium sulfite
t
(211 mg) in BuOH (1.2 mL) and water (1.2 mL). The crude residue
was subjected to gravity silica gel column chromatography
(10e50% EtOAc/hexanes) to yield the diol 44 (74 mg, 58%) as
a white solid as a mixture of chiral/meso diastereomers (27:1).
Recrystallisation of the mixture from CH2Cl2/hexanes removed the
meso isomer. The filtrate was concentrated in vacuo to give the
chiral diol (R,R)-44 (60 mg, 47%), mp 114e115 ꢀC. HPLC analysis
(20% 2-propanol/hexane, retention times (R,R)-diol 44 8.73 min
(major), (S,S)-diol 44 9.39 min (minor)) showed the ee of the (R,R)-
4.5.6. (2S,3S)-1,4-Di(2-tert-butyldimethylsilyloxyphenyl)-2,3-bu-
tandiol 45. The diol (S,S)-454 was synthesised by General
procedure A using alkene 32 (97 mg, 0.207 mmol, E/Z 12:1), AD-
mix
a (290 mg), methanesulfonamide (18 mg, 0.188 mmol) and
t
sodium sulfite (166 mg) in BuOH (1 mL) and water (1 mL). Flash
silica gel column chromatography (1e100% EtOAc/hexanes) iso-
lated the diol 45 (15 mg, 13%) as an oil as a mixture of chiral/meso
diastereomers (12:1), which exhibited identical spectral properties
to the (R,R)-diol. HPLC analysis (2.5% 2-propanol/hexane, retention
times (R,R)-diol 45 13.4 min (minor), (S,S)-diol 45 12.3 min (major))
showed the ee of the (S,S)-diol 45 was 23%.
diol 44 was 8%. 1H NMR (300 MHz)
d
2.21 (d, 2H, J¼6.4 Hz, OH), 2.96
2
3
(dd, 2H, JHH¼13.5 Hz, JHH¼7.5 Hz, CHH), 3.03 (dd, 2H,
2JHH¼13.5 Hz, JHH¼4.2 Hz, CHH), 3.73e3.90 (m, 2H, CHOH),
3
7.23e7.45 (m, 8H, ArH); 13C NMR (300 MHz)
d 34.8 (CH2CH]CH2),
72.8 (CHOH),112.1, 116.4, 120.6, 124.8 (118.5, q, J¼320 Hz, CF3), 121.5
4.5.7. (2R,3R)-1,4-Di(2-nitrophenyl)-2,3-butandiol 48. Compound
(R,R)-48 was synthesised using General procedure A, alkene 35
(ArC6), 128.5 (ArC4), 128.6 (ArC5), 131.1 (ArC2), 132.5 (ArC3), 148.3
(ArC1); FTIR
n
3268 (w),1483 (w),1416 (w),1228 (w),1207 (w),1134
(20 mg, 0.067 mmol, E/Z 18:1), ADmix b (94 mg), meth-
(w), 1096 (w), 903 (w), 809 (w), 772 (w), 635 (w); MS (ES, þve) m/z
561 (100%, MþNa), 556 (15, MþNH4); HRMS (ES, þve) calcd for
C18H20F6O8S2N 556.0535, found 556.0535.
anesulfonamide (6 mg, 0.067 mmol), sodium sulfite (100 mg) and
a 1:1 mixture of BuOH and water (0.7 mL), The crude solid was
t
subjected to flash silica gel column chromatography (20e30%
EtOAc/hexanes) to afford the diol 48 (10 mg, 45%) as a white
solid, mp 132e134 ꢀC, as a mixture of chiral/meso diastereomers
(16:1). HPLC analysis (35% 2-propanol/hexane, retention times (R,
R)-diol 48 19.4 min (major), (S,S)-diol 48 31.0 min (minor))
4.5.4. (2S,3S)-1,4-Di(2-trifluorosulfonylphenyl)-2,3-butandiol
The diol (S,S)-44 was synthesised by General procedure A using
alkene 31 (110 mg, 0.523 mmol, E/Z 3.6:1), ADmix (333 mg),
44.
a

M.J. Gresser et al. / Tetrahedron 66 (2010) 6965e6976
6975
showed the ee of the (R,R)-diol 48 was 58%. 1H NMR (300 MHz)
2-propanol/hexane, retention times (R,R)-diol 50 13.1 min (minor),
(S,S)-diol 50 16.1 min (major)) showed the ee of the (S,S)-diol 50
2
3
d
2.48 (br s, 2H, OH), 3.13 (dd, 2H, JHH¼13.5 Hz, JHH¼8.5 Hz,
2 3
CHH), 3.27 (dd, 2H, JHH¼13.3 Hz, JHH¼3.3 Hz, CHH), 3.90 (dd,
was 73%. 1H NMR (500 MHz)
d
2.05 (br s, 2H, OH), 2.83 (dd, 2H,
3
3
3
2
2H, JHH¼3.0, 7.0 Hz, CHOH), 7.41 (t, 2H, JHH¼7.0 Hz, ArH5), 7.46
2JHH¼13.6 Hz, JHH¼8.3 Hz, CHH), 2.89 (dd, 2H, JHH¼13.6 Hz,
3JHH¼4.3 Hz, CHH), 3.75e3.82 (m, 2H, CHOH), 3.79 (s, 6H, OCH3),
6.77 (s, 2H, ArH2), 6.79e6.82 (m, 4H, ArH4 and ArH6), 7.23 (t, 2H,
(d, 2H, 3JHH¼7.7 Hz, ArH3), 7.57 (t, 2H, 3JHH¼7.5 Hz, ArH4), 7.94 (d,
2H, JHH¼8.2 Hz, ArH6); 13C NMR (75 MHz)
d 37.3 (CH2), 74.1
3
(CHOH), 124.9 (ArC6), 127.8 (ArC5), 133.1 (ArC4), 133.3 (ArC3),
J¼7.8 Hz, ArH5); 13C NMR (125 MHz)
d 40.4 (CH2), 55.2 (OCH3), 74.0
133.4 (ArC2), 149.9 (ArC1); FTIR
n
1513 (w), 1344 (w), 1255 (m),
(CHOH), 111.9 (ArC6), 115.1 (ArC2), 121.7 (ArC4), 129.6 (ArC5), 139.6
1077 (w), 1023 (m, br), 797 (m), 660 (s), 673 (s), 626 (s); MS (ES,
þve) m/z 355 (28, MþNa), 350 (8, MþNH4), 233 (10), 211 (12), 146
(70), 105 (100%); HRMS (ES, þve) calcd for C16H16N2O6Na
355.0906, found 355.0904.
(ArC3), 159.8 (ArC1); FTIR n 3329 (br), 1611 (w), 1583 (m), 1487 (m),
1454 (w), 1264 (m), 1104 (w), 1043 (s), 930 (w), 763 (w); MS (ES,
þve) m/z 325 (100%, MþNa), 320 (90, MþNH4); HRMS (ES, þve)
calcd for C18H22O4Na 325.1416, found 325.1403.
4.5.8. (2S,3S)-1,4-Di(2-nitrophenyl)-2,3-butandiol 48. The diol (S,S)-
47 was synthesised by General procedure A using alkene 35 (20 mg,
4.5.12. (2R,3R)-1,4-Di(3-methoxyphenyl)-2,3-butandiol 50. The diol
(R,R)-50 was synthesised by General procedure A using alkene 37
0.067 mmol, E/Z 18:1), ADmix
a
(94 mg), methanesulfonamide
(98 mg, 0.366 mmol, E/Z 4.3:1), ADmix a (512 mg), meth-
(6 mg, 0.067 mmol), sodium sulfite (100 mg) and a 1:1 mixture of
tBuOH and water (0.68 mL). The crude mixture was subjected to
flash silica gel column chromatography (20e30% EtOAc: hexanes)
to yield the diol (S,S)-48 (4 mg, 18%) as a mixture of chiral/meso
diastereomers (4:1), which was spectroscopically identical to the
(R,R)-48 enantiomer. HPLC analysis (35% 2-propanol/hexane, re-
tention times (R,R)-diol 48 19.4 min (minor), (S,S)-diol 48 30.6 min
(major)) showed the ee of the (S,S)-diol 48 was 44%.
anesulfonamide (35 mg, 0.366 mmol) and sodium sulfite (549 mg)
in a 1:1 mixture of BuOH and water (3.7 mL). The diol (R,R)-50
t
(94 mg, 85%) was purified via flash silica gel column chromatog-
raphy as a white solid, mp 52e56 ꢀC, which had identical spectral
properties to the diol (S,S)-50. HPLC analysis (40% 2-propanol/
hexane, retention times (R,R)-diol 50 12.8 min (major), (S,S)-diol 50
16.2 min (minor)) showed the ee of the (R,R)-diol 50 was 76%.
4.5.13. (2S,3S)-1,4-Di(4-methoxyphenyl)-2,3-butandiol 51.30 The
diol (S,S)-51 was synthesised by General procedure A using alkene 38
4.5.9. (2S,3S)-1,4-Di(2-methoxyphenyl)-2,3-butandiol 49.19 The diol
(S,S)-49 was synthesised by General procedure A using alkene 36
(200 mg, 0.745 mmol, E/Z 6.2:1), ADmix
a (1.043 g), meth-
(75 mg, 0.28 mmol), ADmix
a
(392 mg), methanesulfonamide
anesulfonamide (71 mg, 0.745 mmol) and sodium sulfite (1.113 g) in
a 1:1 mixture of BuOH and water (7.4 mL). The diol (S,S)-50 was
recrystallised from CH2Cl2/hexanes as a white powder (202 mg, 90%)
as a mixture of chiral/meso diastereomers (8.8:1), mp 100e102 ꢀC.30
HPLC analysis (40% isopropanol/hexane, retention times (R,R)-diol 51
12.3 min (minor), (S,S)-diol 51 13.8 min (major)) showed the ee of the
t
(27 mg, 0.28 mmol), sodium sulfite (420 mg) in a 1:1 mixture of
tBuOH and water (2.8 mL). The crude solid was subjected to flash
silica gel column chromatography (10% EtOAc/hexanes to 100%
EtOAc) to yield the diol 49 (44 mg, 52%) as aviscous, colourless oil, as
a mixture of chiral/meso diastereomers (6:1).19 HPLC analysis
(20e40% 2-propanol/hexane, retention times (R,R)-diol 49 22.8 min
(minor), (S,S)-diol 49 26.7 min (major)) showed the ee of the (S,S)-
(S,S)-diol 51 was 85%. 1H NMR (500 MHz)
d 2.01 (br s, 2H, OH), 2.77
(dd, 2H, 2JHH¼13.8 Hz, 3JHH¼8.1 Hz, CHH), 2.84 (dd, 2H, 2JHH¼13.8 Hz,
diol 49 was 34%. 1H NMR (500 MHz)
d
2.66 (br s, 2H, OH), 2.89 (dd,
3JHH¼4.2 Hz, CHH), 2.92
(dd, JHH¼13.9 Hz, JHH¼2.6 Hz, CHH),
*
2
3
2
3
2
2H, JHH¼13.2 Hz, JHH¼7.4 Hz, CHH), 2.92 (dd, 2H, JHH¼13.2 Hz,
3.67e3.69 (m, 2H, CHOH), 3.79 (s, 6H, OCH3), 6.84 (d, 4H, J¼8.5 Hz,
*
3JHH¼4.6 Hz, CHH), 3.05
*
(dd, JHH¼13.8 Hz, JHH¼2.1 Hz, CHH),
ArH2), 7.13 (d, 4H, J¼8.4 Hz, ArH3); 13C NMR (125 MHz)
d 37.4 , 39.4
2
3
3.72e3.73 (m, 2H, CHOH), 3.78 (s, 6H, OCH3), 3.83
*
, 6.85 (d, 2H,
(CH2), 55.2 (OCH3), 74.0 (CHOH), 74.7
*
(CHOH), 114.0 (ArC2), 114.1 ,
*
J¼8.2 Hz, ArH6), 6.89 (t, 2H, J¼7.3 Hz, ArH4), 7.16 (d, 2H, J¼7.3 Hz,
130.0 (ArC4), 130.3 (ArC3), 158.3 (ArC1); FTIR n 3352 (br), 1614 (w),
ArH3), 7.20 (t, 2H, J¼8.5 Hz, ArH5); 13C NMR (125 MHz)
d
33.1
*
, 34.9
1512 (s), 1468 (w), 1248 (s), 1178 (m), 1032 (s), 1021 (s), 804 (s); MS
(ES, þve) m/z 325 (100%, MþNa), 320 (90, MþH); HRMS (ES, þve)
calcd for C18H22O4Na 325.1416, found 325.1407.
(CH2), 55.3 (OCH3), 73.4 (CHOH), 74.3 , 110.4 (ArC6), 120.8 (ArC4),
*
126.9 (ArC2), 127.7 (ArC5), 131.3 (ArC3), 157.4 (ArC1); FTIR
n 1496
(w), 1265 (w),1245 (w), 1055 (w), 853 (w), 828 (w), 815 (w), 753 (s),
745 (s); MS (ES, þve) m/z 325 (50, MþNa), 320 (28, MþNH4), 303
(100%, MþH), 285 (45, MꢂH2O); HRMS (ES, þve) calcd for C18H23O4
303.1596, found 303.1595.
4.5.14. (2R,3R)-1,4-Di(4-methoxyphenyl)-2,3-butandiol 51.30 The
diol (R,R)-51 was synthesised by General procedure A using alkene
38 (200 mg, 0.745 mmol, E/Z 6.2:1), ADmix
b (1.043 g), meth-
anesulfonamide (71 mg, 0.745 mmol) and sodium sulfite (1.113 g)
in a 1:1 mixture of BuOH and water (7.4 mL). The diol (R,R)-51
t
4.5.10. (2R,3R)-1,4-Di(2-methoxyphenyl)-2,3-butandiol 49.19 The
diol (R,R)-49 was synthesised by General procedure A using alkene
(217 mg, 96%) was recrystallised from CH2Cl2/hexanes as a white
powder as a mixture of chiral/meso diastereomers (9.1:1), mp
104e105 ꢀC, which had identical spectral properties to the (S,S)-51
diol. HPLC analysis (40% isopropanol/hexane, retention times (R,R)-
diol 51 12.0 min (major), (S,S)-diol 51 14.1 min (minor)) showed the
ee of the (R,R)-diol 51 was 87%.
36 (75 mg, 0.28 mmol), ADmix
b (392 mg), methanesulfonamide
(27 mg, 0.28 mmol), sodium sulfite (420 mg) in a 1:1 mixture of
tBuOH and water (2.8 mL). Flash silica gel column chromatography
(10e20% EtOAc/hexanes) yielded the diol (R,R)-49 (31 mg, 37%) as
a viscous, colourless oil, which had identical spectral properties to
the diol (S,S)-49. HPLC analysis (20e40% 2-propanol/hexane, re-
tention times (R,R)-diol 49 22.4 min (major), (S,S)-diol 49 26.6 min
(minor)) showed the ee of the (R,R)-diol 49 was 40%.
Acknowledgements
Financial support from UoW small grants schemes is gratefully
acknowledged. MJG and SMW thank the Australian Research
Council for PhD scholarships.
4.5.11. (2S,3S)-1,4-Di(3-methoxyphenyl)-2,3-butandiol 50. The diol
(S,S)-50 was synthesised by General procedure A using alkene 37
(98 mg, 0.366 mmol, E/Z 4.3:1), ADmix
a (512 mg), meth-
anesulfonamide (35 mg, 0.366 mmol) and sodium sulfite (549 mg)
in a 1:1 mixture of BuOH and water (3.7 mL). The crude diol was
Supplementary data
t
subjected to flash silica gel column chromatography to give (S,S)-50
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.06.035.
(85 mg, 77%) a white solid, mp 52e54 ꢀC. HPLC analysis (40%

6976
M.J. Gresser et al. / Tetrahedron 66 (2010) 6965e6976
11. The yields quoted were based on the quantity of each diastereomer present in
References and notes
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