Axially chiral tridentate isoquinoline derived ligands for diethylzinc addition to aldehydes

Article abstract of DOI:10.1016/j.tet.2018.07.048

The synthesis and resolution of new tridentate isoquinoline-derived ligands has been developed. The key steps in the synthetic sequence include successive, chemo-selective Suzuki-Miyaura cross-couplings of 1,3-dichloroisoquinoline with suitable arylboronic acids. The new ligands prepared in this manner were resolved either via molecular complexation with N-benzylcinchonidinium chloride as with 1-[3-(2-hydroxyphenyl)isoquinolin-1-yl]naphthalen-2-ol or via chromatographic separation of its epimeric camphorsulfonates as for 1,3-bis-(2-hydroxynaphthalen-1-yl)isoquinoline. 4-tert-Butyl-2-chloro-6-[1-(2-hydroxymethylnaphthalen-1-yl)isoquinolin-3-yl]phenol was resolved by chiral semi-preparative HPLC. The application of these ligands in the diethylzinc addition to aldehydes was investigated. In certain cases, the desired secondary alcohols were obtained in high yield with excellent enantiomeric excess (ee > 99%) at low catalyst loading (1 mol%).

Full text of DOI:10.1016/j.tet.2018.07.048

Accepted Manuscript
Axially chiral tridentate isoquinoline derived ligands for diethylzinc addition to
aldehydes
Brian A. Sweetman, Patrick J. Guiry
PII:
S0040-4020(18)30892-5
10.1016/j.tet.2018.07.048
TET 29708
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 July 2018
Revised Date: 23 July 2018
Accepted Date: 24 July 2018
Please cite this article as: Sweetman BA, Guiry PJ, Axially chiral tridentate isoquinoline derived ligands
for diethylzinc addition to aldehydes, Tetrahedron (2018), doi: 10.1016/j.tet.2018.07.048.
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ACCEPTED MANUSCRIPT
Axially chiral tridentate isoquinoline derived
Leave this area blank for abstract info.
ligands for diethylzinc addition to aldehydes
Brian A. Sweetman and Patrick J. Guiry*
School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
tBu
Lig.
O
OH
Et
Lig. (1 mol%)
Toluene, 0 oC
Cl
65-99 % yield
Up to 99 %ee
+
ZnEt2
N
OH
OH
R
H
R

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Axially chiral tridentate isoquinoline derived ligands for diethylzinc addition to
aldehydes
Brian A. Sweetman and Patrick J. Guiry*
Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthesis and resolution of new tridentate isoquinoline-derived ligands has been developed.
The key steps in the synthetic sequence include successive, chemo-selective Suzuki-Miyaura
cross-couplings of 1,3-dichloroisoquinoline with suitable arylboronic acids. The new ligands
prepared in this manner were resolved either via molecular complexation with N-
benzylcinchonidinium chloride as with 1-[3-(2-hydroxyphenyl)isoquinolin-1-yl]naphthalen-2-ol
or via chromatographic separation of its epimeric camphorsulfonates as for 1,3-bis-(2-
hydroxynaphthalen-1-yl)isoquinoline. 4-tert-Butyl-2-chloro-6-[1-(2-hydroxymethylnaphthalen-
1-yl)isoquinolin-3-yl]phenol was resolved by chiral semi-preparative HPLC. The application of
these ligands in the diethylzinc addition to aldehydes was investigated. In certain cases, the
desired secondary alcohols were obtained in high yield with excellent enantiomeric excess (ee >
99%) at low catalyst loading (1 mol%).
Available online
Keywords:
Axial chirality
Tridentate ligand
Asymmetric catalysis
Isoquinoline
2018 Elsevier Ltd. All rights reserved
.
Chiral alcohol
1. Introduction
The development of chiral tridentate ligands suitable for
application in a variety of catalytic asymmetric processes has
received much attention in recent years,1-3 including examples
from our own group.4-11 Of these ligands, Carreira’s imine 1
derived from NOBIN12 (2) (Figure 1) has proven extremely
effective in the Ti(IV)-catalyzed enantioselective Mukaiyama
aldol reaction of various ketene acetals with aldehydes as well as
the addition of 2-methoxypropene to aldehydes.13 More recently,
Mao et al. have described the synthesis of sulfamide-amine
Figure 2. Mao’s ligands 3 and 4 and Guiry’s Quinazolinaps 5
Our initial ligand design sought to combine the effective 6-
chelate about the biaryl axis of the Quinazolinaps 5 while
maintaining the tridentate binding mode of ligand 1. Structural
analysis of 1 shows a 6-membered and 7-membered chelate
between the imine nitrogen and, respectively, the phenolic
hydroxyl and the naphthol. The phenol is substituted with a 4-
tert-butyl group and a 2-bromo substituent, with the latter
increasing phenol acidity. We therefore reasoned that 6 would be
a suitable synthetic target as the key design principle was to
incorporate the nitrogen donor into an isoquinoline ring and to
leave the remainder of the ligand mostly unchanged. Simplifying
further, in our preliminary investigations, we decided to
concentrate on the synthesis of analogues 7 and 8 (Figure 3).26
alcohols
3 and 4 (Figure 2) for the highly efficient
enantioselective addition of diethylzinc to aldehydes.14 We have
recently reported a series of bidentate ligands, Quinazolinaps 5,
which give excellent results in a number of catalytic asymmetric
reactions.15-25 Encouraged by these results, a research program
into the design, synthesis, and resolution of a series of ligands
related to the previously reported tridentate ligands and our
Quinazolinaps was initiated.
Figure 1. Carreira’s ligand 1 derived from NOBIN 2.
Figure 3. Original design 6 and its simpler analogues 7 and 8

2
Tetrahedron
ACCEPTED MANUSCRIPT
Synthesis and Resolution
We reasoned that, although our ligands 7 and 8 have no NH
moiety available to form the analogous hydrogen bond, the
existence of a second OH with a proton capable of occupying a
similar region in space might facilitate formation of the
molecular crystal. Gratifyingly, ligand 7 could be resolved by
employing a modified procedure. Therefore, stirring racemic 7
with 0.5 equiv. of 16 in acetone for 18 h produced a white
precipitate of (R)-7 16 that was isolated and converted further to
afford (R)-7 in 36% yield with 90% ee. The mother liquor was
also processed to give the opposite enantiomer in 56% yield and
88% ee. The resolution could be repeated with the
enantioenriched (R)-7 and (S)-7 to furnish each enantiomer in
99% and 98% ee, respectively, (Scheme 2).26
The synthesis of ligands 7 and 8 commenced with the Suzuki-
Miyaura cross-coupling of 1,3-dichloroisoquinoline (9) and
arylboronic acid 10 to yield biaryl 11 (Scheme 1). The
regioselectivity of this cross-coupling reaction has previously
been reported and rationalised by Woodward et al.27 The
preparation of aryl ethers 12 and 13 was completed via Suzuki-
Miyaura cross coupling of 11 with arylboronic acids 14 and 10,
respectively, (Scheme 1). The 3-chloro substituent is generally a
poor electrophilic partner for cross-coupling reactions, however,
when Pd(PPh3)4 was employed as the catalyst, both coupled
products 12 and 13 were obtained in moderate yields of 55% and
45%, respectively, even when forcing conditions were employed
(110 °C in DMF). The emergence of XPhos (15) as an excellent
ligand for the Suzuki-Miyaura cross-coupling reaction of aryl
chlorides and tosylates has greatly expanded the scope of this
useful process.28 Therefore, by heating biaryl 11 with Pd(OAc)2,
XPhos and K3PO4 in THF with the requisite boronic acid at 80
°C for 18 h, the required aryl methyl ethers 12 and 13 were
isolated in excellent yields of 85% and 95%, respectively.
Scheme 2. Optical resolution of ligand 7
Scheme 1. Synthesis of Ligands 7 and 8
X-ray crystal analysis revealed formation of an intramolecular
hydrogen bond between the phenol hydrogen and the
isoquinoline nitrogen of (R)-7 and an intermolecular bond
between the naphthol hydrogen and the chloride anion (Figure 5).
B(OH)2
OMe
PCy2
iPr
14
N
OR
OR
iPr
b, 55%
or c, 85%
15
3
Cl
C40
C41
iPr
C15
C16
N2
C14
C30
N
C39
C28
12: R = Me
7: R = H
C13
C31
d
Cl
C38
1
Cl
C19
C29
C34
C36
C37
83%
C27
N3
C17
C12
N
9
a, 79%
C11
C18
O2
C32
OMe
C33
C35
O1
C10
B(OH)2
OMe
C8
C7
O3
C3
C9
C6
11
C42
C50
C1
C43
C44
Cl
C51
C2
C49
N1
C4
C20
C46
C5
C48
10
C45
C47
C21
C22
N
OR
OR
C26
b, 45%
or c, 95%
C25
C23
13: R = Me
8: R = H
d
91%
Figure 5. X-ray crystal structure of (R)-(+)-7 16 (Hydrogen
atoms and solvent molecules are omitted for clarity).26
Reagents and conditions: (a) Pd(PPh3)4 (cat.), DME, ArB(OH)2,
Na2CO3, 90°C, 5 d (b) Pd(OAc)2 (cat.), 15, ArB(OH)2, K3PO4,
THF, 80°C, 18 h (c) 48% HBr, AcOH, 140 °C, 18 h.
Table 1. Selected bond lengths and angles for (R)-(+)-7 16
Length/Å
2.22
Angle/deg
074.5
Compounds 12 and 13 obtained from the Suzuki-Miyaura
reaction were subsequently exhaustively demethylated with HBr
to afford the desired tridentate ligands 7 and 8 in good yield.29
Subsequently, various resolution methods were investigated.
Ding et al. reported the optical resolution of ligand 2 by
molecular complexation with N-benzylcinchonidinium chloride
(16) (Figure 4).30
H(3O)…Cl
N(3)-C(35)-C(42)-C(51)
C(34)-C(35)-C(42)-C(43)
O(3)-H(3O)...Cl
H(2O)…N(3)
H(2O)…N(3)
1.84
076.3
2.22
172.9
O(2)-H(2O)…N(3)
O(1)-H(1O)…Cl
144.9
166.2
The stereoview of the crystal structure of the (R)-(+)-2 16
shows that hydrogen bonding between the amino alcohol and the
chlorine atom is crucial to formation of the molecular crystal - a
fact that is best illustrated by the failure of biaryl 17, to form an
analogous molecular crystal.
Unfortunately, ligand 8 could not be resolved using this
method. Therefore, racemic 8 was converted to its camphor
sulfonates using the procedure of Chow et al. (Scheme 3).31
Figure 4. N-Benzylcinchonidinium chloride (16) and the
dimethyl derivative of NOBIN 17

3
Scheme 3. Synthesis of epimeric bis(sulfonates) (Sa,S,S)-18 and
(Ra,S,S)-18 and conversion of (Sa,S,S)-18 to (S)-(-)-8
Table 3. The kinetic parameters for the racemisation of 7
ACCEPTED MANUSCRIPT
T (K)
328
106kracem/s-1
008.3 (0.5)a
022 (1.3)
05700(1.7)
300 (13.0)
Eyring Functions
∆H#/kJmol-1
∆S#/J mol-1K-1
∆G#/kJmol-1
99 (24)
-43 (68)
112 (20)
338
348
363
Arrhenius Parameters
Ea/kJ mol-1
102 (24)
260 (8)
ln(A/s-1)
aFigures in parentheses are errors calculated for 95% confidence level
The epimers were then converted to enantiomerically enriched
(+)-8 and (-)-8, by stirring in 50% w/v NaOH at 0 °C, followed
by acidic work-up and extraction into CH2Cl2 (Scheme 4).
Racemic 8 was also resolved via chiral semi-preparative HPLC,
(see Supporting Information).
18
17
16
15
14
13
y = 11.939x - 18.778
R2 = 0.994
Scheme 4. Synthesis of Ligand (S)-8
2.7
2.8
2.9
103/T (K-1)
3.0
3.1
Racemisation Studies
Figure 8. The Eyring plot for the racemisation of 7 in benzene
Table 4. The kinetic parameters for the racemisation of 8
Ligands 7 and 8 are classed as tri-ortho substituted biaryls and
these compounds are known to readily racemise when at least
one of the ortho groups is small such as OMe or F.32 However,
Brown and co-workers have reported the synthesis of phenol 19
(Figure 6) the half-life of which they calculated to be 455 days at
room temperature.33 This compares favourably with the
unsubstituted derivative 20, an intermediate in the synthesis of
Quinap (21), which has a half-life to racemisation of just 29 days
at room temperature, Figure 6. We envisaged that our
compounds, which are structurally close to Brown’s intermediate
19, might display a higher barrier to racemisation due to the
similarity of the substitution pattern on the isoquinoline ring.
T (K)
313
106kracem/s-1
Eyring Functions
∆H#/kJmol-1
∆S#/Jmol-1K-1
∆G#/kJmol-1
007.5 (0.4)a
041 (4)
230 (3)
860 (13)
86 (10)
-88 (29)
112 0(9)
328
348
363
Arrhenius Parameters
Ea/kJ mol-1
ln(A/s-1)
89 (10)
020 (4)
aFigures in parentheses are errors calculated for 95% confidence level
21
y = 10.330x - 13.186
R2 = 0.999
20
19
18
17
16
15
Figure 6. Brown’s intermediates 19 and 20 and Quinap (21)
Spivey et al. have reported the atropisomerisation studies of a
series of axially chiral biaryl derivatives of DMAP.34,35 Following
the method of Eyring and Cagle, they studied the
atropisomerisation of individual enantiomers of these ligands in
sealed-tube experiments followed by CSP HPLC analysis.36 We
therefore applied this method in our investigations into the
racemisation of ligands 7 and 8. Arrhenius and Eyring plots were
graphed and kinetic parameters for the racemisation of 7 and 8
were obtained (Tables 3-4, Figures 8-9).
2.7
2.9
3.1
3.3
103/T (K-1)
Figure 9. The Eyring plot for the racemisation of 8 in benzene
From these data it can be calculated that for ligand 7 the half-life
to racemisation at room temperature is 97 days and that an
enantiomerically homogeneous sample would lose 1% of its
optical purity after 34 h. For ligand 8 these values are 105 days
and 37 h, respectively. The barriers to atropisomerisation for
these two ligands are arguably too low to render them useful for
application in asymmetric catalysis at room temperature.
However, their use at temperatures below ambient might still be
possible although not practical. Ligand 8 was therefore applied in
the diethylzinc addition to benzaldehyde at –20 °C with varying
catalyst loadings to afford the desired product as a racemate in
only moderate yield. In order to explain the moderate yields and
racemic nature of the product it is worthwhile investigating the
mechanism of the diethylzinc addition. It has been proposed that
the mechanism for the bidentate ligand 22 in the diethylzinc

4
Tetrahedron
addition proceeds through an alkoxide dimer 23 which then
acid 32. The resulting cross-coupled product may then be
ACCEPTED MANUSCRIPT
dissociates into a reactive monomer 24 which ensures high
converted to 30 (Scheme 7).
reactivity (Scheme 5).
Scheme 7. Retrosynthetic Analysis of ligand 30
Scheme 5. The mechanism for bidentate ligands in the
diethylzinc addition
However, with a potentially tridentate system the key design
feature is to create a more rigid structure that might better
discriminate between the two enantiotopic faces of benzaldehyde
within the transition-state complex. If one considers the
momomeric tridentate binding mode of ligand 7, i.e., complex
27, (Scheme 6). It has been shown that such monomers, in the
case of bidentate ligands, are the reactive components in the
addition process.37,38
The preparation of boronic acid 32 began with the
bromination of 4-tert–butyl-phenol 37 to produce the desired
ortho-brominated product 38 in 99% yield. This compound was
then chlorinated following the procedure of Sheldon et al. to
yield phenol 39 in 95% yield.40 Methylation of 39 following a
modification of the procedure of Cram and co-workers afforded
aryl ether 40 in 92% yield.41 The synthesis of the desired boronic
acid 32 was then completed by formation of the Grignard reagent
and subsequent quenching with trimethylborate, followed by
hydrolysis (Scheme 8).
Scheme 6. Monomeric tridentate binding mode of ligand 7
Scheme 8. Synthesis of boronic acid 32
However, it has previously been shown that the PdCl2
complex of the structurally related compound 28 contains a
palladium-nitrogen bond which is 26° out of the isoquinoline ring
plane. This distortion is required to accommodate the constraints
of the chelate unit. It may be reasoned therefore that, based on
this observation and on molecular models of the monomer 27,
that the ligand may not form the desired complex but may instead
bind the zinc ion in a bidentate fashion preferably adopting a six-
chelate binding mode as in 29 (Scheme 6). This bidentate binding
mode would have little influence on the level of
enantioselectivity of zinc addition, as chiral information would
not be efficiently transferred from the chiral axis. We therefore
proposed ligand 30 as a suitable candidate to offset all the
difficulties encountered with ligands 7 and 8 and which still
incorporates key features of the successful Carreira ligand 1
(Figure 10). Interestingly, Baker and co-workers have previously
described the synthesis and resolution of ligand 31 and its
application in the diethylzinc addition to benzaldehyde producing
the desired alcohol in 91% yield and 68% ee.39
Reagents and conditions: (a) Br2, 0 °C, CH2Cl2, 1 h, 99%. (b)
SO2Cl2, diisobutylamine, toluene, 70 °C, 95%. (c) K2CO3, MeI,
Me2CO, 70 °C, 24 h, 92%. (d) (i) Mg, THF; (ii) B(OMe)3, -78
°C, 18 h; (iii) H2O.
Compound 35 was synthesised in 81% yield by Suzuki-
Miyaura cross-coupling between aryl chloride 9 and arylboronic
acid 36 (Scheme 9). The synthesis of intermediate 33 was
completed by a similar coupling of aryl chloride 35 and boronic
acid 32. As with the analogous aryl chloride used in the synthesis
of ligands 7 and 8, this compound reacted to produce the desired
compound in only a moderate yield of 40% even under forcing
conditions of DMF at 110 ºC. Attempts to offset this poor
reactivity by the use of XPhos (15) were unsuccessful due to its
poor selectivity in the cross-coupling reaction. The resulting
compound 33 was then dibrominated to yield compound 41 in
near quantitative yield. This compound was subsequently
converted to aldehyde 34 in a very disappointing 12% yield.
Due to the moderate yield of the cross-coupling reaction and
the poor yield in the synthesis of the aldehyde 34, we decided to
investigate an alternative approach, by functionalising the methyl
substituent on the naphthyl ring prior to cross-coupling. The 2-
bromo-biaryl 42 was synthesised in 72% yield in an identical
manner to its 3-chloro substituted analogue 35 as we envisage
that the aryl bromide 42 would be more reactive in the proposed
Suzuki-Miyaura cross-coupling than aryl chloride 35. To this
end, the synthetic strategy (Scheme 10) was developed where
compounds 43 and 44 are key intermediates.
Figure 10. Baker’s ligand 31 and our proposed tridentate ligand
30
Synthesis and Resolution
Our initial strategy involved the synthesis of ligand 30 via
selective cross-coupling of 1,3-dichloroisoquinoline and
arylboronic acid 9 followed by a cross-coupling with arylboronic

5
Scheme 9. Synthesis of aldehyde 34
°C temperatures. By making a simple approximation (∆S# = 0),
ACCEPTED MANUSCRIPT
it is possible to estimate the Gibbs free energy for this ligand,
which is calculated as ∆G# = 164.6 kJ mol-1. The half-life to
racemisation at room temperature may be estimated using this
value to be around 777 million years!
Diethylzinc Addition
Scheme 11. General scheme for the addition of diethylzinc to
benzaldehyde
The synthesis of 43 and 44 was achieved following an identical
procedure to that previously described for aldehyde 34.
Dibromination of 35 was completed in 96% yield, followed by
conversion of the dibromide 45 to aldehyde 43 in 65% yield. The
related 3-bromo derivative 46 was synthesized in 97% yield
whilst the aldehyde 44 was prepared in 68% yield. The Suzuki-
Miyaura cross-coupling of compound 43 proceeded in a
moderate yield of 50% whereas the brominated derivative 44
gave the desired product in an improved yield of 67%. The
resulting aryl ether 34 was demethylated using HBr/AcOH to
afford the desired phenol 47 in 67% yield. The synthesis was
completed by reduction of the aldehyde to give the desired ligand
30 in 92% yield.
In order to study the effectiveness of the two classes of ligands
(8 and 30), they were employed initially in the diethylzinc
addition to benzaldehyde (Scheme 11).42 A number of factors
influencing the effectiveness of both ligands were of interest,
including the catalyst loading and the reaction temperature (Table
5).
Table 5a,b Diethylzinc addition to benzaldehyde catalysed by
ligands 8 and 30
Mol
(%) of
Ligand
Yield
of 47
(%)
Temp
(°C)
ee of
47 (%)
Entry
Ligand
Config.
1
2
-20
-20
-20
-20
-20
-20
0
S-(8)
S-(8)
10
50
60
60
85
99
99
98
99
91
0
0
-
-
Scheme 10. Synthesis of ligand 30
5
3
S-(8)
1
0
-
4
S-(30)
S-(30)
S-(30)
R-(30)
S-(30)
S-(30)
10
98
>99
99
98
91
0
S
S
S
R
S
-
5
5
1
6
7b
8
5
rt
0.1
0.0001
9
rt
aAll reactions carried out in toluene for 40 to 45 h. bConfiguration
assigned by comparison with literature values. Enantiomeric excesses
were determined using chiral HPLC.
Unlike ligand 8, the related ligand 30 gave excellent results
even at 1 mol%. At -20 °C, the catalyst loading was varied from
10 mol% to 1 mol%, with excellent enantioselectivities in each
case (entries 4-6). Even at 0.1 mol% the ligand produces the
desired alcohol in nearly quantitative yield with the enantiomeric
excess reduced to 91% (entry 8). At 0 °C with 5 mol% of 30, the
yield and enantiomeric excess were 98% (entry 7). The decrease
of enantiomeric excess to 91% in the case of the 0.1 mol%
reaction at room temperature may be due to competition between
the background process and the catalytic asymmetric pathway. It
is known that at 0 °C this non-catalytic pathway is “shut down”
although at room temperature it may be active. This suggestion is
reinforced when only 0.001 mol% of the ligand was employed at
room temperature. In this instance the desired alcohol is
produced in 91% yield but without asymmetric induction, entry
9. By analogy to the mechanism outlined for 8 it may be
reasoned that the incorporation of a methylene unit permits the
formation of a rigid tridentate monomeric complex of the form
48, Figure 11.
Various attempts at resolving ligand 30 via complexation with
N-benzylcinchonidinium chloride 16 were unsuccessful.
Fortunately, ligand 30 proved resolvable via chiral semi-
preparative HPLC. The absolute configuration of ligand 30 was
assigned tentatively based on analogy between the signs of the
optical rotation of both hands of ligand 30 with the sign of the
optical rotation of the (R)- and (S)-enantiomers of Baker’s ligand
31.
Racemisation Study
The racemisation study of phenol 30 was first attempted using
the same procedure as outlined for the first two ligands 7 and 8.
Interestingly, even at 120 °C overnight no racemisation was
observed. By increasing the temperature to 180 °C, however, the
enantioenriched ligand began to racemise at an appreciable rate.
Due to the high barrier to rotation about the chiral axis of
compound 30 at 180°C it is evident that its racemisation at room
temperature would be exceedingly slow. It was therefore decided
not to examine the racemisation of 30 at other, higher than 180

6
Tetrahedron
increasing the catalyst loading gave higher yield and
ACCEPTED MANUSCRIPT
enantiomeric excess (99 and 98%ee, respectively), entries 8 and
9. trans-Cinnamaldehyde 52, gave both high yield (86%) and
enantiomeric excess (88%). For the more electron-rich substrates,
4-methoxybenzaldehyde 54 and ferrocenealdehyde 53, the
enantioselectivities dropped to 70% and 82% ee, respectively,
entries
5
and 6. Interestingly, the electron poor
pentafluorobenzaldehyde 55, entry 7, gave the desired product in
a moderate yield of 60% and an enantiomeric excess of 62%. The
aliphatic aldehyde 3-phenylpropanal 56, entry 10. gave the
product in a good yield of 81% and an excellent enantiomeric
excess of 97%. This is quite an impressive result since aliphatic
aldehydes generally give poorer levels of enantioselectivities in
the diethylzinc addition. The propargyl aldehyde 57, entry 2,
gave an excellent yield of product albeit with poor
enantioselectivity (20 %ee). This is not uncommon for linear
aldehydes where differentiation between the two enantiotopic
faces of the aldehyde is difficult.
Figure 11. Tridentate monomeric complex 48
As a result of the effectiveness of 30 at low loadings and low
temperature we decided to perform a substrate scope by variation
of the aldehydic substrates (49-57), Table 6. The isomeric
naphthaldehydes 49 and 50, entries
1 and 2, and 4-
chlorobenzaldehyde 51, entry 3 gave good yields and excellent
enantioselectivities (95-98 %ee). In the case of 1-naphthaldehyde
49 and 4-chlorobenzaldehyde 51, lowering the temperature, and
Table 6a Diethylzinc addition to various aldehydes catalysed by 30
Entry
Aldehyde
Ligand
Time (h)
Yield (%)
ee (%)
Config.
1
2
1-naphthaldehyde (49)
2-naphthaldehyde (50)
(S)-30
(S)-30
(S)-30
(S)-30
(R)-30
(R)-30
(R)-30
(R)-30
(R)-30
(R)-30
(R)-30
36
36
40
36
40
40
40
48
48
48
48
74
95
65
86
65
82
60
91
99
81
90
95
98
95
88
82
70
62
99
98
97
20
S
S
3
4-chlorobenzaldehyde (51)
trans-cinnamaldehyde (52)
ferrocenealdehyde (53)
S
4
S
5 b,c
6
R
R
R
R
R
R
R
4-methoxybenzaldehyde (54)
pentafluorobenzaldehyde (55)
1-naphthaldehyde (49)
7c
8d
9d
10d
11d
4-chlorobenzaldehyde (51)
3-phenylpropanal (56)
phenylpropargyl aldehyde (57)
aAll reactions carried out in toluene with 1mol% of 30, at 0 °C. Enantiomeric excess determined by HPLC analysis using an OD or OD-H chiralcel column.
c
bEnantiomeric excess determined using an AD chiralpak column. No literature values for configuration available and product configuration assigned by
analogy to other aryl aldehydes. dReactions carried out with 2 mol% of 30 at -20 ºC.
Conclusion
The synthesis and resolution of three tridentate ligands has
graphs. Ligand 8 was applied in the diethylzinc addition to
benzaldehyde to produce the secondary alcohol in moderate yield
but without asymmetric induction. In contrast, the application of
ligand 30 in the diethylzinc addition to benzaldehyde was
investigated and afforded the desired alcohol in excellent yield
with near perfect enantioselectivities at low catalyst loadings.
Ligand 30 was also applied in the diethylzinc addition to a
variety of other aldehydes, providing the desired secondary
alcohols in good yields with moderate to excellent enantiopurity.
been described. All three ligands were synthesized using
selective, successive Suzuki-Miyaura cross-coupling reactions.
Resolution was achieved by a range of techniques including
molecular complexation for ligand 7 as well as conversion of the
ligand to its epimeric camphor sulfonates as in the case of ligand
8. Ligands 8 and 30 were also resolved via semi-preparative
HPLC. The barrier to racemisation about the chiral axis of the
three ligands was investigated via racemisation studies and
Arrhenius and Eyring plots were graphed. The half-life to
racemisation at room temperature was extrapolated from these
Experimental Section
All commercially available solvents were purified and dried
before use. Diethyl ether and tetrahydrofuran were distilled from

7
sodium/benzophenone and dichloromethane was distilled from
calcium hydride. Ammonium hydroxide was purchased as a 28%
solution of NH3 in H2O. 1-Bromo-2-methylnaphthalene was
purchased as 90% technical grade and was used without any
further purification. Where necessary other solvents and reagents
used were purified according to known procedures.43 DMF and
DME were degassed using three freeze-thaw cycles prior to use.
Oxygen-free nitrogen was obtained from BOC gases. Flash
chromatography was performed using Merck Kieselgel 60 (Art.
9385) and aluminium oxide 90, standardised (activity II-III).
Merck precoated Kieselgel 60F254 and alumina (neutral, type E)
were used for thin layer chromatography. High-resolution mass
spectrometry (HRMS) measurements are valid to ±5 ppm.
was added and the suspension was allowed stir for a further 1 h.
ACCEPTED MANUSCRIPT
The reaction mixture was evaporated in vacuo and
dichloromethane (100 mL) was added. The organic layer was
separated, and the aqueous layer was washed with
dichloromethane (4 × 50 mL). The combined organic extracts
were dried over MgSO4 and filtered. The solvent was removed
in vacuo to give a brown solid, which was stirred in pentane
overnight producing the title compound 10 (8.04 g, 86%) as a
white powder. m.p. 116-118 °C (lit.45 m.p. 117-119 °C); 1H NMR
(300 MHz; d6-DMSO) δ = 8.27 (s, 2H, B(OH)2), 7.89-7.81 (m,
2H), 7.69 (d, 1H, J = 8.3 Hz), 7.44-7.28 (m, 3H), and 3.85 (s,
OCH3); 13C NMR (75 MHz; d6-DMSO) 159.0 (4°), 136.2 (4°),
129.8, 128.9 (4°), 128.4, 127.8 (2C), 126.3, 123.5, 114.1, 56.6
(OMe); IR (KBr) νmax 3350, 1589, 1512, 1333, 1244, and 1063
cm-1.
1,3-Dichloroisoquinoline (9)
Method 1
Method 246
Phenylphosphonic dichloride (7.0 mL, 48 mmol) was added
drop-wise with stirring to homophthalimide (0.94 g, 5.8 mmol).
The mixture was then heated to 130 °C for 2 h during which time
the initial aggregate turned to a dark brown solution. The solution
was allowed to cool and water (35 mL) was added drop-wise
[Caution!] with stirring. Diethyl ether (50 mL) was added and
the organic layer was separated. The aqueous layer was extracted
with diethyl ether (3 × 30 mL). The ether layers were combined,
washed with 1 M NaOH (2 × 20 mL), water (20 mL), brine (20
mL), dried over MgSO4, filtered and evaporated in vacuo to yield
the title compound 9 as an off-white solid (0.91 g, 79%). Rf =
n-Butyllithium (7.0 mL, 2.5 M in hexanes, 18 mmol) was
added dropwise to
a
stirred solution of 1-bromo-2-
methoxynaphthalene (3.78 g, 15.9 mmol) in dry Et2O (60 mL) at
-78 °C under an atmosphere of nitrogen. The solution was
warmed to room temperature and stirred for 1 h. After this time,
the flask was re-cooled to -78 °C and trimethylborate (2.3 mL, 21
mmol) was added drop-wise. The mixture was allowed warm to
room temperature overnight (18 h) under nitrogen. 1M HCl (50
mL) was added dropwise and the solution was stirred for an
additional 1 h. The reaction mixture was evaporated in vacuo and
extracted with dichloromethane (3 × 30 mL). The combined
organic layers were washed with brine (30 mL) and dried over
Na2SO4. The solution was filtered and concentrated in vacuo to
produce a light brown solid that was stirred in pentane for 2 h,
filtered and dried in vacuo to give the title compound 10 (2.64 g,
82%) as an off-white powder which was identical to a previously
prepared sample.
1
0.70, (CH2Cl2); m.p. 121-123 °C (lit.44 120-121 °C); H NMR
(300 MHz; CDCl3) δ = 8.27 (dd, 1H, J1 = 8.4 Hz, J2 = 0.9 Hz),
7.77-7.75 (m, 2H), 7.69-7.64 (m, 2H); 13C NMR (75 MHz;
CDCl3) 151.1 (4°), 143.3 (4°), 139.4 (4°), 132.4, 129.0, 126.8,
126.5, 125.9 (4°), 120.0; IR (KBr) νmax 2918, 1553, and 746 cm-1.
Method 2
3-Chloro-1-(2-methoxynaphthalen-1-yl)isoquinoline (11)15
To homophthalic acid (12.50 g, 69.4 mmol) was added
ammonium hydroxide (15.8 mL, 0.16 mol). This mixture was
vacuum distilled until a brown solid remained and then heated
gently at normal pressure with a Bunsen burner until an orange
oil resulted. The flask was allowed to cool and phenylphosphonic
dichloride (30 mL, 0.21 mol) was added and the mixture heated
to 160 °C for 3 h after which time the resultant solution was
cooled and poured onto ice water [Caution!]. The solution was
extracted with dichloromethane (3 × 100 mL) and the organic
layer was washed sequentially with 20% NaOH (2 × 50 mL),
water (50 mL), brine (50 mL), and then dried over MgSO4. The
organic layer was filtered and evaporated in vacuo to yield the
crude product which was purified by column chromatography
over silica gel (CH2Cl2) to give the title compound 9 (10.3 g,
75%), which was identical to a sample prepared according to
method 1.
1,3-Dichloroisoquinoline 9 (6.85 g, 34.6 mmol) was added to
a dry Schlenk tube under nitrogen followed by Pd(PPh3)4 (2.00 g,
0.73 mmol) and stirred under vacuum. Anhydrous, degassed
DME (150 mL) was added and the mixture was stirred for 15
min. Arylboronic acid (10) (7.00 g, 34.6 mmol), dissolved in the
minimum amount of degassed ethanol (50 mL), was then added.
Sodium carbonate solution (35 mL, 2 M) was added and a white
precipitate was formed instantly. The yellow mixture was
refluxed at 90 ºC for 5 d. The reaction mixture was cooled to
room temperature and water (100 mL) and dichloromethane (100
mL) were added. The organic layer was separated and
concentrated in vacuo to give a brown oil which was re-dissolved
in dichloromethane (100 mL), washed with water (50 mL), brine
(30 mL), and then dried over MgSO4. The solution was filtered
and evaporated in vacuo to give a dark brown solid which was
stirred in diethyl ether (50 mL) for 1 h and filtered to give the
title compound 11 as an off-white solid (9.5 g, 86%). This
material was used without any further purification. Rf = 0.30, 2:1
2-Methoxy-1-naphthaleneboronic acid (10)
Method 1
(CH2Cl2:pentane); m.p. 172-173 °C (lit.15 m.p. 159-160 °C); H
1
Magnesium (5.00 g, 0.21 mol) was activated by heating and
stirring in vacuo for 1 h at 80 °C after which time it was allowed
to cool to room temperature. Dry THF (20 mL) was added under
NMR (300 MHz; CDCl3) δ = 8.00 (d, 1H, J = 8.9 Hz), 7.86-7.81
(m, 3H), 7.66 (dd, 1H, J1 = 6.9 Hz, J2 = 1.3 Hz), 7.48 (d, 1H, J =
8.5 Hz), 7.42-7.24 (m, 4H), 7.04 (d, 1H, 8.1 Hz), 3.76 (s, 3H,
OCH3); 13C NMR (75 MHz; CDCl3) 159.10 (4°), 154.9 (4°),
145.1 (4°), 138.3 (4°), 133.6 (4°), 131.1, 130.9, 129.0 (4°), 128.0,
127.7, 127.3, 127.01 (4°), 127.02, 126.1, 124.6, 123.8, 120.6
(4°), 119.3, 113.3, 56.5 (OMe); IR (KBr) νmax 1621, 1576, 1547,
1510, 1264, and 1069 cm-1; HRMS (ES+): calculated mass
320.0842, found 320.0840; C20H14ClNO: calculated C, 75.12; H,
4.41; N, 4.38, found, C, 75.12; H, 4.44; N, 4.28
an atmosphere of nitrogen.
A solution of 1-bromo-2-
methoxynaphthalene (10.9 g, 46.3 mmol) in THF was then added
slowly via cannula to give a black suspension. The mixture was
heated with a heat gun at regular intervals during the addition
period. The solution was then allowed to stir for 1 h at room
temperature. The resulting mixture was added slowly via cannula
to a solution of triisopropylborate (14.6 mL, 63.3 mmol) in THF
(20 mL) at -78 °C. The reaction mixture was allowed to warm to
room temperature while stirring overnight (18 h). Water (40 mL)

8
Tetrahedron
2-Methoxyphenylboronic acid (14)
Method 1
Magnesium (5.30 g, 0.22 mol), was activated by heating and
gel (CH2Cl2) to yield the title compound 12 (0.40 g, 55%) as a
ACCEPTED MANUSCRIPT
white solid. Rf = 0.40, (CH2Cl2); m.p. 146-148 °C; 1H NMR (300
MHz; CDCl3) δ = 8.28 (s, 1H, H4), 8.00-7.91 (m, 3H), 7.85 (d,
1H, J = 7.7 Hz), 7.62 (app t, 1H, J = 7.9 Hz), 7.50 (d, 1H, J = 8.3
Hz), 7.42 (d, 1H, 9.0 Hz), 7.36-7.23 (m, 5H), 7.03 (app t, 2H, J =
7.5 Hz), 3.92 (s, 3H), 3.76 (s, 3H); 13C NMR (75 MHz; CDCl3)
157.4 (4°), 157.2 (4°), 154.9 (4°), 149.0 (4°), 136.7 (4°), 134.1
(4°), 131.9, 130.3, 129.9, 129.6 (4°), 129.3(2C), 127.9, 127.5
(4°), 127.4, 127.3, 126.8, 126.6, 125.3, 123.6, 122.6 (4°), 121.1,
120.7, 113.8, 111.4, 56.8 (OMe), 55.7 (OMe); IR (KBr) νmax
1621, 1598, 1267, 1250, 1023, and 760 cm-1; HRMS (ES+):
calculated for C27H21NO2, 392.1651; found, 392.1667;
C27H21NO2: calculated C, 82.84; H, 5.41; N, 3.58, found, C,
82.60; H, 5.43; N, 3.48.
stirring under nitrogen for 1 h at 90 °C after which time it was
allowed to cool to room temperature and dry THF (30 mL) was
added. A solution of 2-bromoanisole (5.0 mL, 42 mmol) in dry
THF (50 mL) was added slowly via syringe to give a black
suspension. The solution was allowed to stir for 1 h at room
temperature. The reaction mixture was then added slowly, via
cannula filtration, to a solution of triisopropylborate (15 mL, 43
mmol) in THF (15 mL) at -78 °C. The reaction mixture was
allowed to warm to room temperature while stirring overnight
(18 h). Water (60 mL) was added and the suspension was
allowed to stir for a further 1 h. The reaction mixture was
evaporated in vacuo and dichloromethane (100 mL) was added.
The organic layer was separated, and the aqueous layer was
extracted with dichloromethane (4 × 50 mL). The combined
organic extracts were dried over MgSO4 and filtered. The solvent
was removed in vacuo to give a light green solid, which was
stirred in pentane producing the title compound 14 (4.40 g, 69%)
as a white powder. m.p. 109-111 °C; 1H NMR (300 MHz;
CDCl3) δ = 7.87 (dd, 1H, J1 = 7.4 Hz, J2 = 1.9 Hz), 7.45 (ddd,
1H, J1 = 11.7 Hz, J2 = 4.5 Hz, J3 = 2.5 Hz), 7.03 (app t, 1H, J =
7.2 Hz), 6.91 (d, 1H, J = 8.4 Hz), 6.63 (s, 2H, B(OH)2), 3.90 (s,
3H, OCH3); 13C NMR (75 MHz; CDCl3) 164.5 (4°), 136.9, 132.9,
121.3, 110.0, 55.5 (OMe); IR (KBr) νmax 3384, 1601, 1412, 1229,
1164, 1055, 1024, 756, and 658 cm-1.
Method 227
Biaryl 11 (320 mg, 1.00 mmol) was added to a dry Schlenk
tube under nitrogen followed by Pd(PPh3)4 (58 mg, 50 µmol) and
stirred under vacuum. Anhydrous, degassed DMF (10 mL) was
added under nitrogen and the mixture was heated to 55 °C to
form a yellow solution. Arylboronic acid 14 (0.167 g, 1.1 mmol)
and Cs2CO3 (489 mg, 1.50 mmol) were then added sequentially
and the mixture heated to 100 °C for 39 h. The mixture was
cooled to room temperature and water (10 mL) and diethyl ether
(30 mL) were added. The organic layer was extracted and
concentrated in vacuo to give a brown oil which was re-dissolved
in diethyl ether (30 mL), washed with water (20 mL), brine (20
mL), and then dried over MgSO4. The solution was filtered and
evaporated in vacuo to give a dark brown oil. The oil was then
purified by column chromatography over silica gel (CH2Cl2) to
yield the title compound 12 (0.175 g, 45%) as a white solid
which was identical to a previously prepared sample.
Method 2
n-Butyllithium (10.6 mL, 2.5 M in hexanes, 26.5 mmol), was
added drop-wise to a stirred solution of 2-bromoanisole (3.0 mL,
24 mmol) in dry diethyl ether (20 mL) at -78 °C under an
atmosphere of nitrogen. The solution was warmed to 0 °C and
stirred for 1 h after which time it was re-cooled to -78 °C and
trimethylborate (3.5 mL, 31 mmol) was added drop-wise. The
mixture was allowed to warm to room temperature overnight (18
h) under nitrogen. 1 M HCl (30 mL) was added drop-wise and
the solution was stirred for 1 h. The reaction mixture was
evaporated in vacuo and then extracted with dichloromethane (3
× 30 mL). The combined organic layers were washed with brine
(20 mL) and dried over Na2SO4. The solution was filtered and
evaporated in vacuo to produce a light green solid. The solid was
stirred in pentane for 2 h, filtered and the resulting white powder
was dried in vacuo to give the title compound 14 (2.25 g, 69%),
which was identical to a previously prepared sample.
Method 328
Biaryl 11 (0.20 g, 0.63 mmol), Pd(OAc)2 (2.8 mg, 1.3 µmol),
XPhos (11.9 mg, 31 µmol), 14 (0.19 g, 1.25 mmol) and K3PO4
(0.40 g, 1.88 mmol) were placed in a 20 mL Schlenk tube which
was then evacuated and backfilled with nitrogen. This process
was repeated an additional two times. Dry THF (1.5 mL) was
added and the mixture was heated overnight (18 h) with stirring
at 80 °C. Water (5 mL) and ethyl acetate (20 mL) were added and
the phases were separated and the aqueous layer was extracted
with additional portions of ethyl acetate (3 × 5 mL). The
combined organic layers were washed with brine (20 mL) and
dried over Na2SO4, filtered and evaporated under reduced
pressure to yield the crude product which was purified by column
chromatography over silica gel (5:1, pentane:EtOAc) to yield the
title compound 12 (234 mg, 96%) as a white solid which was
identical to a previously prepared sample.
1-(2-Methoxynaphthalen-1-yl)-3-(2-methoxyphenyl)isoquinoline
(12)
Method 115
1,3-Bis-(2-methoxynaphthalen-1-yl)isoquinoline (13)
Biaryl 11 (0.60 g, 1.88 mmol) was added to a dry Schlenk
tube under nitrogen followed by Pd(PPh3)4 (0.143 g, 0.124 mmol)
and stirred under vacuum. Anhydrous, degassed DMF (20 mL)
was added under nitrogen and the mixture was stirred for 15 min.
Arylboronic acid 14 (286 mg, 1.88 mmol), dissolved in the
minimum amount of degassed ethanol (3 mL), was then
transferred to the Schlenk tube. Sodium carbonate (1.9 mL, 2 M)
was added and the mixture was heated at 110 ºC for 3 d. The
mixture was cooled to room temperature and water (30 mL) and
diethyl ether (50 mL) were added. The organic layer was
separated and concentrated in vacuo to give a brown oil which
was re-dissolved in diethyl ether (50 mL), washed with water (20
mL), brine (20 mL), and then dried over MgSO4. The solution
was filtered and concentrated in vacuo to give a dark brown oil
which was then purified by column chromatography over silica
Method 1
Biaryl 11 (0.32 g, 1 mmol) was added to a dry Schlenk tube
under nitrogen followed by Pd(PPh3)4 (58 mg, 50 µmol) and
stirred under vacuum. Anhydrous, degassed DMF (10 mL) was
added under nitrogen and the mixture was heated to 55 °C to
form a yellow solution. Arylboronic acid 10 (0.17 g, 1.1 mmol)
and Cs2CO3 (0.49 g, 1.5 mmol) were then added sequentially to
the Schlenk tube and the mixture was heated to 100 °C for 39 h.
The mixture was cooled to room temperature and water (10 mL)
and diethyl ether (30 mL) were added. The organic layer was
extracted and concentrated in vacuo to give a brown oil which
was re-dissolved in diethyl ether (30 mL), washed with water (20
mL), brine (20 mL), and then dried over MgSO4. The solution
was filtered and evaporated in vacuo to give a dark brown oil.

9
The oil was purified by column chromatography over silica gel
(CH2Cl2) to yield the title compound 13 (0.175 g, 45%) as a
white solid. Rf = 0.20, (3:1 pentane:EtOAc); m.p. 208-210 °C; 1H
NMR (300 MHz; CDCl3) δ = 7.97-7.75 (m, 6H), 7.71-7.65 (m,
2H), 7.59 (d, 1H, J = 8.3 Hz), 7.43-7.25 (m, 8H), 3.86 (s, 3H),
3.81 (s, 3H); 13C NMR (75 MHz; CDCl3) 157.8, 155.1, 154.7,
148.8, 136.8, 134.1, 133.9, 130.3, 130.1, 129.8, 129.3, 129.2,
127.9, 127.8, 127.6, 127.4, 127.2, 127.1, 126.6, 126.4, 125.3,
125.2, 124.9, 123.6, 123.5, 122.5, 122.4, 114.3, 113.9, 57.1
(OMe), 56.9 (OMe); IR (KBr) νmax 1621, 1593, 1511, 1268,
1251, 1084, 807, and 748 cm-1; HRMS (ES+): calculated for
C31H23NO2, 442.1807, found 442.1821; C31H23NO2: calculated C,
84.33; H, 5.25; N, 3.17, found, C, 83.83; H, 5.17; N, 3.08.
washed with brine (10 mL) and dried over Na2SO4. The organic
ACCEPTED MANUSCRIPT
layer was filtered and evaporated in vacuo to yield the crude
product which was purified by column chromatography over
silica gel (5:1 pentane:EtOAc) to yield the title compound 8 (111
mg, 91%) as a yellow solid. Rf = 0.20, (3:1 pentane:EtOAc); m.p.
226-228 °C; 1H NMR (300 MHz; CDCl3) δ = 8.37 (d, 1H, J = 8.6
Hz), 8.27 (s, 1H, H4), 7.98 (d, 1H, J = 8.2 Hz), 7.86-7.70 (m,
5H), 7.63 (d, 1H, J = 8.4 Hz), 7.52-7.16 (m, 8H); 13C NMR (75
MHz; CDCl3) 156.1 (4°), 154.7 (4°), 152.4 (4°), 148.9 (4°), 137.7
(4°), 133.1 (4°), 131.9 (4°), 131.5, 131.3, 131.2, 129.5 (4°),
128.84 (4°), 128.81, 128.3, 128.1, 127.8, 127.6, 127.04, 127.00,
126.8 (4°), 124.7, 123.8, 123.6, 123.2, 122.7, 119.5, 118.5, 117.3
(4°), 115.7 (4°); IR (KBr) νmax 3222, 1620, 1589, 1494, 1436,
1346, 1262, 1242, 882, 816, 756, and 738 cm-1; HRMS (ES+):
calculated for C29H19NO2, 414.1494, found 414.1512;
C29H19NO2: calculated C, 84.24; H, 4.63; N, 3.39, found C,
83.75; H, 4.69; N, 3.31; HPLC AD semi-preparative column, 4.7
mL/min, pentane:IPA 70:30, 40 °C, tR(S) 8.7 min, tR(R) 14.0 min.
Method 2
Biaryl 11 (0.20 g, 0.63 mmol), Pd(OAc)2 (2.8 mg, 1.3 µmol),
XPhos (11.9 mg, 31 µmol), 10 (0.253 g, 1.25 mmol) and K3PO4
(0.40 g, 1.9 mmol) were placed in a 20 mL Schlenk tube which
was then evacuated and backfilled with nitrogen. This process
was repeated an additional two times. Dry THF (1.5 mL) was
added and the mixture was heated overnight (18 h) with stirring
at 80 °C. Water (5 mL) and ethyl acetate (30 mL) were added and
the organic layer was separated. The aqueous layer was extracted
with ethyl acetate (3 × 5 mL) and the combined organic layers
were washed with brine (20 mL) and dried over Na2SO4. The
organic layer was filtered and concentrated in vacuo to yield the
crude product which was purified by column chromatography
over silica gel (CH2Cl2) to yield the title compound 13 (0.236 g,
86%) as a white solid which was identical to a previously
prepared sample.
Resolution
of
1-[3-(2-hydroxyphenyl)isoquinolin-1-
yl]naphthalen-2-ol (7)30
Racemic biaryl 7 (93 mg, 0.26 mmol) was placed in a 50 mL
flask and acetone (2 mL) was added, followed by N-
benzylcinchonidinium chloride 16 (54 mg, 0.19 mmol). The
mixture was allowed to stir overnight (18 h) at room temperature
producing a white precipitate (R)-(+)-7·16. The precipitate was
filtered, washed with acetone and then stirred in a 3M
HCl/EtOAc biphasic mixture (10 mL) until all the precipitate had
dissolved. The organic layer was then separated, washed with
brine (5 mL), dried over Na2SO4, filtered and evaporated in
vacuo to yield (R)-(+)-7 (33.5 mg, 36% yield, 90% ee). The
mother liquor was worked up in an identical manner to yield (S)-
(-)-7 (52.1 mg, 56% yield, 88% ee). This entire process was
repeated with enantioenriched 7 to yield (R)-(+)-7 and (S)-(-)-7 in
98% and 99% ee respectively. αD = (R) +48.0, (S) –47.0, (CHCl3,
c=1.0); HPLC AD semi-preparative column, 4.7 ml/min,
pentane:IPA, 70:30, 40 °C tR(S) = 8.7 min, tR(R) = 14.0 min.
1-[3-(2-Hydroxyphenyl)isoquinolin-1-yl]naphthalen-2-ol (7)29
Aryl ether 12 (0.13 g, 0.33 mmol) was placed in a 20 mL
Schlenk tube, 48% HBr (1.2 mL) and acetic acid (1.5 mL) were
added sequentially and the resultant solution was heated to 140
°C overnight (18 h). The Schlenk tube was allowed to cool and
water (5 mL) was added followed by dichloromethane (20 mL).
The organic layer was separated and the aqueous layer was
washed with dichloromethane (2 × 5 mL). The combined organic
layers were washed with brine (10 mL) and dried over Na2SO4.
The organic layer was filtered and evaporated in vacuo to yield
the crude product which was purified by column chromatography
over silica gel (3:1 pentane:EtOAc) to yield the title compound 7
(0.10 g, 83%) as a yellow solid. Rf = 0.20, (3:1 pentane:EtOAc);
Epimeric bis(sulfonates) (Ra,S,S)-18 and (Sa,S,S)-1831
To a solution of diol 8 (100 mg, 0.242 mmol) in dry
dichloromethane (2 mL) was added dry triethylamine (84 µL,
0.61 mmol) at 0 °C. After 15 min at this temperature
camphorsulfonyl chloride (151 mg, 0.61 mmol) was added and
the resultant solution was allowed to warm to room temperature
with stirring overnight (18 h). Water (5 mL) was added and the
reaction mixture was extracted with dichloromethane (3 × 10
mL). The combined extracts were washed with brine (10 mL),
dried over Na2SO4, filtered and evaporated in vacuo. This crude
material was purified by column chromatography over silica gel
(5:1 to 1:1 pentane:EtOAc) to yield a mixture of the epimeric
bis(sulfonates) 18 (190 mg, 93%). The epimers were separated
by column chromatography over silica gel (pentane-EtOAc 3:1)
to afford four main fractions, the yields and diastereomeric
excesses for which are shown in Table 2.
1
m.p. 223-227 °C; H NMR (300 MHz; CDCl3) δ = 8.67 (s, 1H,
H4), 8.19 (d, 2H, J = 8.1), 8.07-7.94 (m, 2H), 7.82 (app t, 1H, J =
7.0 Hz), 7.62 (d, 1H, J = 8.4 Hz), 7.55-7.44 (m, 2H), 7.37-7.25
(m, 3H), 7.09 (d, 1H, J = 8.0 Hz), 6.97 (app t, 1H, J = 7.3 Hz),
6.86 (d, 1H, J = 8.3 Hz); 13C NMR (75 MHz; CDCl3) 159.6,
155.5, 152.9, 150.9, 137.9, 133.8, 131.4, 130.8, 130.7, 128.7,
128.2, 127.7, 127.6, 127.5, 127.3, 127.0, 126.5, 123.9, 123.2,
119.8, 118.9, 118.4, 118.2, 117.4, 115.4; IR (KBr) νmax 3246,
2925, 1591, 1505, 1436, 1348, 1262, 883, 816, and 758 cm-1;
HRMS (ES+): calcd. for C25H17NO2, 364.1338, found 364.1347;
C25H17NO2: calculated C, 82.63; H, 4.72; N, 3.85, found C,
82.22; H, 4.75; N, 3.90; HPLC OD-H Column, 1 ml/min, 80:20
pentane:IPA, 40 °C, tR(R) = 7.3 min, tR(S) = 11.7 min.
1,3-Bis-(2-hydroxynaphthalen-1-yl)-isoquinoline (8)
Biaryl 13 (0.13 g, 0.29 mmol) was placed in a 20 mL Schlenk
tube. To this were added 8% HBr (1.1 mL) and acetic acid (1.5
mL) and the resultant solution heated to 140 °C overnight (18 h).
The resulting mixture was allowed to cool and water (5 mL) was
added followed by dichloromethane (20 mL). The organic layer
was separated and the aqueous layer was washed with
dichloromethane (2 × 5 mL). The combined organic layers were
Table 2. Yields and diastereomeric excesses for (Sa,S,S)-18
and (Ra,S,S)-18

10
Tetrahedron
Fraction
ee each. Absolute configuration was assigned based on analogy
de (A%)CCEPTED MANUSCRIPT
Yield (%)
with 7; αD = (R)-8 +103, (S)-8 –103 (CHCl3, c=1.0).
1
2
3
4
17
24
14
21
98 (Sa,S,S)-18
79 (Sa,S,S)-18
84 (Ra,S,S)-18
95 (Ra,S,S)-18
2-Methyl-1-naphthaleneboronic acid (36)
Method 1
aAbsolute configuration was tentatively assigned by analogy between
the sign of the optical rotation of (S)-(-)-7 and (-)-8 which was obtained
from fraction 1 by removal of the auxiliaries.
Magnesium (4.50 g, 0.19 mol) was activated by heating and
stirring in vacuo for 1 h at 80 °C after which time it was allowed
to cool to room temperature and dry THF (20 mL) was added
under an atmosphere of nitrogen. A solution of 1-bromo-2-
methylnaphthalene (5.5 mL, 32 mmol) in dry THF (20 mL) was
slowly added via cannula to give a black suspension. The
solution was heated with a heat gun at regular intervals during
the addition period. The solution was allowed to stir for 1 h at
room temperature. The Grignard solution was then added slowly,
via cannula filtration, to a solution of triisopropylborate (11.0
mL, 47.6 mmol) in THF (20 mL) at -78 °C. The reaction mixture
was allowed to warm to room temperature while stirring
overnight (18 h). Water (30 mL) was added and the suspension
was allowed stir for a further 1 h. The reaction mixture was
reduced in vacuo to remove the THF and dichloromethane (100
mL) was added. The organic layer was separated, and the
aqueous layer was washed with dichloromethane (3 × 20 mL).
The combined organic extracts were dried over Na2SO4 and
filtered and the solvent was removed in vacuo to give a yellow
oil. Conc. HCl (1 mL) was added and the mixture was stirred in
pentane overnight producing a white powder which was filtered
and dried in vacuo to yield the title compound 36 (4.8 g, 81%).
(Sa,S,S)-18
Rf = 0.20, (3:1 pentane-EtOAc); m.p. 240-243 °C; 1H NMR (300
MHz; CDCl3) δ = 8.10-7.88 (m, 7H), 7.81-7.71 (m, 3H), 7.52-
7.32 (m, 7H), 3.59-3.45 (m, 2H), 2.99 (d, 1H, J = 12.7 Hz), 2.63
(d, 1H, J = 13.9 Hz), 2.26-2.02 (m, 4H), 1.96-1.72 (m, 6H), 1.41-
1.23 (m, 4H), 0.61 (s, 3H), 0.46 (s, 3H), 0.32 (s, 3H), 0.07 (s,
3H); 13C NMR (125 MHz; CDCl3) 213.6, 213.3, 156.1, 147.3,
146.0, 145.4, 136.7, 133.7, 133.6, 132.4, 132.1, 131.1, 130.9,
130.5, 130.4, 128.5, 128.3, 128.3, 128.0, 127.9 (2C), 127.8,
127.7, 127.6, 127.5, 126.6, 126.5, 126.4, 123.9, 120.6, 114.3,
58.1, 57.9, 48.5 (2C) (CH2), 47.9, 47.8, 43.0 (CH2), 42.9 (CH2),
42.6, 42.5, 27.0 (2C) (CH2), 25.4 (CH2), 25.2 (CH2), 19.5 (CH3),
19.4 (CH3), 19.4 (CH3), 19.2 (CH3); HPLC AD semi-prep
column, 4.7 ml/min, 80:20 Pentane:IPA, 40 °C, tR = 22.7 min; αD
= + 80.0 (CHCl3, c=1.0); IR (KBr) νmax 2958, 1747, 1371, 1169,
955, 823 and 754 cm-1; HRMS (ES+): calculated for
C49H47NO8S2, 842.2821, found 842.2833; C49H47NO8S2:
calculated C, 69.89; H, 5.63; N, 1.66, found C, 69.23; H, 5.73; N,
1.54.
1
m.p. 128-131 °C (lit.47 m.p. 125-128 °C); H NMR (300 MHz;
d6-DMSO) δ = 8.45 (s, 2H, B(OH)2), 7.81 (ddd, 3H, J1 = 4.0 Hz,
J2 = 7.8 Hz, J3 = 12.2 Hz), 7.50-7.40 (m, 2H), 7.33 (d, 1H, J =
8.5 Hz), and 2.49 (s, CH3); 13C NMR (75 MHz; d6-DMSO) 136.8
(4°), 135.3 (4°), 131.3 (4°), 128.6, 128.5, 128.3, 127.63, 127.62
(4°), 125.9, 125.0, 22.8 (CH3); IR (KBr) νmax 3301, 1427, 1397,
1356, 1333, 1307, 1066, and 810 cm-1.
(Ra,S,S)-18
1
Rf = 0.20, (3:1 pentane-EtOAc); m.p. 145-150 °C; H NMR
(500 MHz; CDCl3) δ = 8.10 (s, 1H), 8.02 (dd, 2H, J1 = 9.2 Hz, J2
= 4.8 Hz), 7.94 (app t, 2H, J = 8.9 Hz), 7.89 (dd, 1H, J1 = 6.0 Hz,
J2 = 3.2 Hz), 7.81 (d, 1H, J = 8.9 Hz), 7.74 (dt, 2H, J1 = 12.0 Hz,
J2 = 7.0 Hz, J3 = 3.0 Hz), 7.56 (d, 1H, J = 8.6 Hz), 7.51-7.48 (m,
4H), 7.40 (dd, 2H, J1 = 14.9 Hz, J2 = 8.6 Hz), 3.55 (d, 1H, J =
14.2 Hz), 3.12 (d, 1H, J = 14.9 Hz), 2.97 (d, 1H, J = 14.6 Hz),
2.86 (d, 1H, J = 14.0 Hz), 2.24-2.12 (m, 3H), 1.98-1.73 (m, 7H),
1.33-1.22 (m, 4H), 0.84 (s, 3H), 0.73 (s, 3H), 0.45 (s, 3H), 0.33
(s, 3H); 13C NMR (125 MHz; CDCl3) 213.6, 213.2, 156.0, 147.1,
145.9, 145.3, 136.7, 133.6, 133.5, 132.4, 132.1, 131.1, 130.8,
130.5, 130.4, 128.5, 128.3, 128.2, 128.1, 128.0, 127.8, 127.8,
127.6, 127.6, 126.7, 126.6, 126.5, 126.4, 124.0, 121.3, 121.1,
58.2 (CH2), 58.0 (CH2), 48.7 (2C), 47.9, 47.8, 43.0 (2C), 42.5
(2C, CH2), 26.9 (2C, CH2), 25.6 (CH2), 25.5 (CH2), 19.8 (CH3),
19.6 (CH3), 19.4 (CH3), 19.3 (CH3); HPLC AD semi-prep
column, 4.7 ml/min, 80:20 pentane:IPA, 40 °C, tR = 30.1 min; αD
= -32.0 (CHCl3, c=1.0); R (KBr) νmax 2959, 1748, 1373, 1168,
954, 823, and 754 cm-1; HRMS (ES+): calculated for
C49H47NO8S2, 842.2821, found 842.2807.
Method 2
n-Butyllithium (19.3 mL, 2.5 M in hexanes, 48 mmol), was
added dropwise to
a
stirred solution of 1-bromo-2-
methylnaphthalene (7.3 mL, 47 mmol) in dry THF (80 mL) at -
78 °C under an atmosphere of nitrogen. The solution was
warmed to room temperature and stirred for 1 h. After this time
the flask was re-cooled to -78 °C and trimethylborate (7.9 mL, 70
mmol) was added dropwise. The mixture was allowed warm to
room temperature overnight (18 h) under nitrogen. HCl (50 mL,
1 M) was added dropwise and the solution was stirred for 1 h.
The reaction mixture was reduced in vacuo and extracted with
dichloromethane (3 × 50 mL). The combined organic layers were
washed with brine (30 mL) and dried over Na2SO4. The solution
was filtered and evaporated in vacuo to produce a yellow oil.
Conc. HCl (1 mL) was added and the mixture was stirred in
pentane overnight producing a white suspension. The precipitate
was filtered and dried in vacuo to yield the title compound 36
(4.52 g, 52%), which was identical to a previously prepared
sample.
(-)-1,3-Bis-(2-hydroxynaphthalen-1-yl)-isoquinoline (-)-(8)
(Sa,S,S)-18 (56 mg, 66 µmol) was dissolved in methanol (5
mL) and 50% w/v NaOH (1 mL) was added at 0 °C. Stirring was
continued for a further 1 h at this temperature. The mixture was
then acidified with HCl (10 mL, 2 M) and extracted with
dichloromethane (3 × 10 mL). The organic layers were
combined, washed with brine (20 mL), dried over Na2SO4,
filtered and evaporated in vacuo. This crude material was
purified by column chromatography over silica gel (3:1,
pentane:EtOAc) to yield the title compound (-)-8 (21.2 mg, 76%)
which was identical to a previously prepared sample. Racemic 8
3-Chloro-1-(2-methylnaphthalen-1-yl)isoquinoline (35)
Method 1
Pd(PPh3)4 (0.80 g, 0.67 mmol) was added to a dry Schlenk
tube containing anhydrous, degassed DME (100 mL) followed by
1,3-dichloroisoquinoline 9 (4.45 g, 22.5 mmol) and the mixture
stirred under nitrogen for 10 min. Arylboronic acid 36 (4.6 g, 25
mmol) was then added as a solid followed by Cs2CO3 (7.5 g, 50
mmol). The mixture was then refluxed at 90 °C for 2 d after
which time it was cooled to room temperature and water (100
mL) and dichloromethane (100 mL) were added. The organic
was also resolved via semi-preparative HPLC using
CHIRALPAK AD column to yield both (-)-8 and (+)-8 in >99%
a

11
layer was extracted and concentrated in vacuo to give a brown oil
which was re-dissolved in dichloromethane (100 mL), washed
with water (30 mL), brine (30 mL), and then dried over Na2SO4.
The solution was filtered and evaporated in vacuo to give an oil
which was purified by column chromatography over silica gel
(2:1, pentane:CH2Cl2) to yield the title compound 35 (5.54 g,
3062, 1693, 1618, 1549, 1311, 1227, 1093, and 750 cm-1;
ACCEPTED MANUSCRIPT
HRMS (ES+): calculated for C20H12ClNO; 318.0686, found
318.0690.
1,3-Dibromisoquinoline
To homophthalic acid (12.0 g, 66.3 mmol) was added
ammonium hydroxide (30 mL, 0.31 mol) and the mixture was
vacuum distilled until a brown solid remained. The solid was
heated gently at ambient pressure with a Bunsen burner until an
orange oil remained. The flask was allowed to cool and PBr3 (6.3
mL, 66 mmol) was added and the mixture was heated at 160 °C
with stirring overnight (18 h). The resultant solution was cooled
and poured onto ice water [Caution!]. The solution was extracted
with dichloromethane (3 × 100 mL) and the organic layer was
washed sequentially with 20% NaOH (2 × 50 mL), water (50
mL) and brine (50 mL). The organic layer was dried over
MgSO4, filtered and evaporated in vacuo to yield crude product
that was purified by column chromatography over silica gel
(CH2Cl2) to yield the title compound (6.0 g, 31%). Rf = 0.70,
1
81%). Rf = 0.50, (3:1 pentane:EtOAc); m.p. 129-131 °C; H
NMR (300 MHz; CDCl3) δ = 7.91-7.83 (m, 4H), 7.68 (dt, 1H, J1
= 1.9 Hz, J2 = 6.0 Hz, J3 = 14.0 Hz), 7.47-7.32 (m, 4H), 7.24 (dd,
1H, J1 = 7.0 Hz, J2 = 8.2 Hz), 6.98 (d, 1H, J = 8.6 Hz), 2.16 (s,
3H, CH3); 13C NMR (75 MHz; CDCl3) 161.5 (4°), 145.2 (4°),
138.4 (4°), 134.5 (4°), 133.4 (4°), 132.7 (4°), 132.0 (4°), 131.3,
128.8, 128.6, 128.0, 127.7, 127.4, 127.2 (4°), 126.4, 126.3, 125.4,
125.1, 119.2, 20.2 (CH3); IR (KBr) νmax 3054, 1547, 1310, 1146,
1093, 965, 865, 812, and 742 cm-1; HRMS (ES+): calculated for
C20H14ClN, 304.0893, found 304.0892; C20H14ClN: calculated C,
79.07; H, 4.65; N, 4.61, found C, 78.79; H, 4.39; N, 4.53.
3-Chloro-1-(2-dibromomethylnaphthalen-1-yl)isoquinoline (45)48
1
To biaryl 35 (3.80 g, 12.5 mmol) was added N-
bromosuccinimide (4.60 g, 26.3 mmol), dibenzoyl peroxide
(70%, 0.44 g, 1.3 mmol) and CCl4 (100 mL). The mixture was
heated to reflux while being irradiated with a UV lamp overnight
(18 h). The resultant mixture was filtered and the precipitate
washed with benzene (2 x 20 mL). The mother liquors were
combined and washed sequentially with water (20 mL) saturated
NaSO3 (20 mL) and brine (20 mL) and then dried over MgSO4.
The organic layer was filtered and evaporated in vacuo to yield
the title compound 45, (5.5 g, 96%) a brown solid, which was
(CH2Cl2); m.p. 151.0-153.0 °C (lit.49 147.0-147.5 °C); H NMR
(300 MHz; CDCl3) δ = 8.26 (m, 1H), 7.85 (s, 1H, H4), 7.77-7.67
(m, 3H); 13C NMR (75 MHz; CDCl3) 144.1 (4°), 138.9 (4°),
132.7 (4°), 132.1, 129.1, 128.9, 128.0 (4°), 126.2, 124.2 (4°); IR
(KBr) νmax 1569, 1544, 1483, 1432, 1288, 1247, 1078, 965, 818
and 747 cm-1; HRMS (ES+): calculated for C9H5Br2N; 285.8867,
found 285.8869; C9H5Br2N: calculated C, 37.67; H, 1.76; N,
4.88, found C, 37.67; H, 1.56; N, 4.70.
3-Bromo-1-(2-methylnaphthalen-1-yl)isoquinoline (42)
used without any further purification. Rf
= 0.50, (2:1
Pd(PPh3)4 (1.09 g, 0.94 mmol) was added to a dry Schlenk
tube containing anhydrous, degassed DME (100 mL) followed by
1,3-dibromoisoquinoline (4.45 g, 22.5 mmol) and the mixture
stirred under nitrogen for 15 min at 70 °C to give a pale yellow
solution. Arylboronic acid 36 (3.85 g, 20.7 mmol) was then
added as a solid followed by Cs2CO3 (6.29 g, 41.4 mmol). The
orange mixture was then refluxed at 90 ºC for 2 d after which
time it was cooled to room temperature and water (100 mL) and
diethyl ether (100 mL) were added. The organic layer was
separated and concentrated in vacuo to give a brown oil which
was re-dissolved in diethyl ether (100 mL), washed with water
(20 mL), brine (20 mL), and then dried over MgSO4. The
solution was filtered and evaporated in vacuo to give the crude
product which was purified by column chromatography over
silica gel (1:1 CH2Cl2:pentane) to yield the title compound 42
(4.75 g, 72%). Rf = 0.2, (1:1 CH2Cl2:pentane); m.p. 138.0-140.0
1
CH2Cl2:pentane); m.p. 186-187 °C; H NMR (300 MHz; CDCl3)
δ = 8.10 (d, 1H, J = 8.9 Hz), 8.01 (d, 1H, J = 8.9 Hz), 7.83-7.84
(m, 3H) 7.6 (ddd, 1H, J1 = 1.9 Hz, J2 = 6.6 Hz, J3 = 10.3 Hz),
7.40 (ddd, 1H, J1 = 1.2 Hz, J2 = 6.79 Hz, J3 = 9.1 Hz), 7.34-7.16
(m, 4H), 6.86 (dd, 1H, J1 = 0.70 Hz, J2 = 8.42 Hz), 6.17 (s, 1H);
13C NMR (75 MHz; CDCl3) 157.9, (4°) 145.4 (4°), 138.4 (4°),
137.4 (4°), 133.6 (4°), 131.9, 131.2 (4°), 130.6, 130.0 (4°),
128.09, 128.14, 127.5, 127.4, 127.2 (4°), 126.8, 126.4, 126.1,
120.4 and 38.8 (1C obscured); IR (KBr) νmax 1549, 1314, 1140,
and 748 cm-1; HRMS (ES+): calculated for C20H12Br2ClN;
459.9103, found 459.9118; C20H12Br2ClN: calculated C, 52.04;
H, 2.62; N, 3.03, found C, 51.74; H, 2.54; N, 2.82.
1-(3-Chloroisoquinolin-1-yl)naphthalene-2-carbaldehyde (43)48
To compound 45 (1.85 g, 4.0 mmol) was added EtOH (20
mL) and THF (12 mL) and the solution was heated to reflux.
AgNO3 (2.00 g, 11.7 mmol) in water (5.6 mL) was added drop-
wise with stirring to produce a yellow precipitate. The reaction
was refluxed for a further 1 h and filtered hot. The precipitate
was washed with hot THF (20 mL), the filtrates were combined
and concentrated, dichloromethane (50 mL), was added followed
by water (20 mL), and the organic layer was separated and the
aqueous layer extracted with dichloromethane (2 × 20 mL). The
organic layers were combined, washed with brine (20 mL) and
dried over Na2SO4. The organic layer was filtered and evaporated
in vacuo to yield the crude product which was purified by
column chromatography over silica gel (10:1 pentane:EtOAc) to
yield the title compound 43 (0.82 g, 65%); Rf = 0.40, (5:1
1
°C; H NMR (300 MHz; CDCl3) δ = 8.00 (s, 1H. H4), 7.90-7.82
(m, 3H), 7.65 (m, 1H), 7.45 (d, 1H, J = 8.4 Hz), 7.40-7.30 (m,
1H), 7.23 (m, 1H), 6.99 (d, 1H, J = 8.4 Hz), 2.11 (s, 3H, CH3);
13C NMR (75 MHz; CDCl3) 161.7 (4°), 138.4 (4°), 135.4 (4°),
134.6 (4°), 133.5 (4°), 132.8 (4°), 132.0 (4°), 131.4, 123.9, 128.7,
127.9, 127.5, 127.4 (4°), 126.5, 126.2, 125.5, 125.1, 123.4, 20.2
(CH3); IR (KBr) νmax 3051, 1544, 1310, 1145, 1089, 962, 841,
812 and 754 cm-1; HRMS (ES+): calculated for C20H14BrN;
348.0388, found 348.0398; C20H14BrN: calculated C, 68.98; H,
4.05; N, 4.02, found C, 68.58; H, 4.02; N, 3.95.
3-Bromo-1-(2-dibromomethylnaphthalen-1-yl)isoquinoline (46)
To biaryl 42 (4.66 g, 13.4 mmol) was added N-bromosuccinimide
(5.0 g, 28.1 mmol) and dibenzoyl peroxide (70%, 0.46 g, 1.3
mmol) followed by CCl4 (100 mL). The mixture was heated to
reflux while being irradiated with a UV lamp overnight (18 h).
The resultant mixture was filtered and the precipitate washed
with benzene (2 × 20 mL). The mother liquors were combined,
washed sequentially with water (20 mL), saturated NaSO3 (20
mL) and brine (20 mL) and then dried over MgSO4. The organic
layer was filtered and evaporated in vacuo to yield the title
1
pentane:EtOAc); H NMR (300 MHz; CDCl3) δ = 9.66 (s, 1H,
COH), 8.15 (d, 1H, J = 8.6 Hz), 8.08 (d, 1H, J = 8.6 Hz), 7.97 (d,
1H, J = 8.2 Hz), 7.91 (app d, 2H, J = 8.8 Hz), 7.71 (app dt, 1H,
J1 = 0.9 Hz, J2 = 7.6 Hz), 7.60 (app t, 1H, J = 7.0 Hz), 7.42-7.33
(m, 3H), 7.22 (d, 1H, J = 8.5 Hz); 13C NMR (75 MHz; CDCl3)
190.8, 157.8 (4°), 145.0 (4°), 141.1 (4°), 138.0 (4°), 136.2 (4°),
132.3 (4°), 132.2 (4°), 131.8, 129.9, 129.1, 128.4, 128.3, 127.5,
127.1 (2C), 126.4, 122.53, 122.49 (4°), 120.2; IR (KBr) νmax

12
Tetrahedron
ACCEPTED MANUSCRIPT
compound 46 (6.60 g, 97%) as a brown solid, which was used
mL, 0.132 mmol) was added. The solution was allowed to stir for
without any further purification. Rf = 0.55, (2:1 CH2Cl2:pentane);
m.p. 191-193 °C; 1H NMR (300 MHz; CDCl3) δ = 8.18 (d, 1H, J
= 8.8 Hz), 8.10-8.07 (m, 2H), 7.92-7.87 (m, 2H), 7.72 (ddd, 1H,
J1 = 1.3 Hz, J2 = 6.7 Hz, J3 = 8.2 Hz), 7.49 (ddd, 1H, J1 = 1.2 Hz,
J2 = 7.0 Hz, J3 = 8.2 Hz), 7.44-7.25 (m, 3H), 6.95 (d, 1H, J = 7.9
Hz), 6.26 (s, 1H); 13C NMR (75 MHz; CDCl3) 158.0 (4°), 138.4
(4°), 137.4 (4°), 135.4 (4°), 133.6 (4°), 131.9, 131.2 (4°), 130.7,
129.9 (4°), 128.3, 128.2, 127.5, 127.5 (2C), 127.4 (4°), 126.9,
126.3, 126.2, 124.5, 38.9; IR (KBr) νmax 1544, 1142, and 750 cm-
1; HRMS (ES+): calculated for C20H12Br3N; 503.8598, found
503.8596; C20H12Br3N: calculated C, 47.47; H, 2.39; N, 2.77,
found C, 47.07; H, 2.12; N, 2.55.
an additional 30 min. Water (30 mL) was added and the organic
layer separated. The aqueous layer was extracted with
dichloromethane (2 × 20 mL) and all organic layers were
combined, washed with brine (30 mL), dried over Na2SO4,
filtered and evaporated in vacuo to afford the title compound 39
(32.9 g, 95 %) as a yellow oil which was used without any
1
further purification. Rf = 0.70, (3:1 pentane:EtOAc); H NMR
(300 MHz; CDCl3) δ = 7.39 (d, 1H, J = 2.1 Hz) 7.80 (d, 1H, J =
2.1 Hz), 5.72 (s, 1H, OH), 1.27 (s, 9H, C-(CH3)3); 13C NMR (75
MHz; CDCl3) 146.2 (4°), 145.5 (4°), 128.4, 126.1, 120.1 (4°),
109.8 (4°), 34.4 (4°), 31.2 -(CH3)3; IR (KBr) νmax 3512, 2964,
1565, 1482, 1395, 1279, 1169, and 768 cm-1; HRMS (ES-):
calculated for C10H12BrClO; 260.9682, found 260.9678.
1-(3-Bromoisoquinolin-1-yl)naphthalene-2-carbaldehyde (44)
1-Bromo-5-tert-butyl-3-chloro-2-methoxybenzene (40)
To dibromide 46 (0.6 g, 1.2 mmol) was added EtOH (6 mL) and
THF (4 mL) and the solution was heated to reflux. AgNO3 (0.59
g, 3.5 mmol) in water (1.7 mL) was added drop-wise with stirring
to produce a yellow precipitate. The reaction was refluxed for a
further 1 h and the hot mixture was filtered and the precipitate
was washed with hot THF (2 × 20 mL). The filtrate was
concentrated and dichloromethane (50 mL) was added followed
by water (20 mL), the organic layer was separated and the
aqueous layer washed with dichloromethane (2 × 20 mL). The
organic layers were combined, washed with brine (20 mL), dried
over Na2SO4, filtered and evaporated in vacuo to yield the crude
product which was purified by column chromatography over
silica gel (2:1 CH2Cl2:Pentane) to yield the title compound 44
(0.29 g, 68%) as a white solid. Rf = 0.45, (3:1 pentane:EtOAc);
To phenol 39 (10.50 g, 39.9 mmol) was added anhydrous
acetone (100 mL) followed by anhydrous K2CO3 (16.6 g, 138
mmol) and methyl iodide (7.5 mL, 120 mmol). The mixture was
refluxed for 24 h and the solvent was removed in vacuo. Water
(50 mL) and dichloromethane (100 mL) were added and the
organic layer was separated. The aqueous layer was extracted
again with dichloromethane (2 × 30 mL) and all organic layers
were combined, washed with brine (30 mL) and dried over
Na2SO4. The organic layer was filtered and evaporated in vacuo
to yield the title compound 40 (10.2 g, 92%) as a yellow oil
which was used without any further purification. Rf = 0.8, (3:1
1
pentane:EtOAc); H NMR (300 MHz; CDCl3) δ = 7.44 (d, 1H, J
= 2.4 Hz), 7.32 (d, 1H, J = 2.2 Hz), 3.87 (s, 3H, CH3), 1.29 (s,
9H, -(CH3)3; 13C NMR (75 MHz; CDCl3) 150.7 (4°), 149.4 (4°),
129.0, 128.4 (4°), 126.9, 117.9 (4°), 60.6 (CH3), 34.6 (4°), 31.1
(CH3)3; IR (KBr) νmax 2964, 1546, 1479, 1275, 999, and 769 cm-1
1
m.p. 145-146 °C; H NMR (300 MHz; CDCl3) δ = 9.66 (s, 1H,
CHO), 8.17-8.07 (m, 3H), 7.98 (d, 1H, J = 8.0 Hz), 7.90 (d, 1H, J
= 8.3 Hz), 7.73 (app t, 1H, J = 7.6 Hz), 7.61 (app t, 1H, J = 7.8
Hz), 7.45-7.32 (m, 3 H), 7.22 (d, 1H J = 8.56 Hz); 13C NMR (75
MHz; CDCl3) 190.8, 157.9, 141.0, 137.9, 136.1, 135.0, 132.3,
132.2, 131.7, 129.9, 129.1, 128.5, 128.4, 127.5, 127.1, 126.3,
124.2, 122.52, 122.47, 122.45; IR (KBr) νmax 1693, 1544, 1316,
1227, 1088, 823, and 748 cm-1; HRMS (ES+): calculated for
C20H12BrNO; 362.0181, found 362.0163; C20H12BrNO:
calculated C, 66.32; H, 3.34; N, 3.87, found C, 66.38; H, 3.35; N,
3.83.
5-tert-Butyl-1-chloro-2-methoxy-3-phenylboronic acid (32)
Magnesium (5.00 g, 0.21 mol) was activated by heating and
stirring in vacuo for 1 h at 80 °C after which time it was allowed
to cool to room temperature and dry THF (20 mL) was added
under an atmosphere of nitrogen. A solution of aryl bromide 40
(7.0 mL, 36 mmol) in dry THF (50 mL) was added slowly via
cannula to give a black suspension. The solution was heated with
the aid of a heat gun at regular intervals during the addition
period. The solution was allowed to stir for 1 h at room
temperature. The Grignard solution was then added slowly, via
cannula filtration, to a solution of triisopropylborate (12.5 mL,
54.0 mmol) in THF (20 mL) at -78 °C. The reaction mixture was
allowed to warm to room temperature while stirring overnight
(18 h). Water (30 mL) was added and the suspension was
allowed to stir for a further 1 h. The reaction mixture was
reduced in vacuo to remove the THF and dichloromethane (100
mL) was added. The organic layer was separated, and the
aqueous layer was washed with dichloromethane (3 × 30 mL),
the combined organic extracts were evaporated in vacuo to give a
yellow oil. NaOH (20% w/v) was added producing a white
precipitate that was stirred in pentane overnight (18 h) and then
filtered using a sintered glass funnel. The precipitate was washed
with more pentane, removed from the funnel and stirred in an
HCl (1 M)/CH2Cl2 biphasic mixture. The organic layer was
separated and the aqueous layer extracted with dichloromethane
(3 × 50 mL). All organic layers were combined, washed with
water (20 mL), brine (20 mL) and dried over Na2SO4. The
organic layer was filtered and evaporated in vacuo to yield
slightly crude product which was purified by column
chromatography over silica gel 10:1 (pentane:EtOAc) to yield the
title compound 32 (4.40 g, 50%) as an oil that solidified upon
standing. Rf = 0.4, (3:1 pentane:EtOAc); m.p. 65-67 °C; 1H NMR
(300 MHz; CDCl3) δ = 7.74 (d, 1H, J = 2.4 Hz) 7.49 (d, 1H, J =
2-Bromo-4-tert-butylphenol (38)
To 4-tert-butyl-phenol (37) (20.1 g, 0.134 mol) was added
dichloromethane (200 mL) and the mixture stirred until all of the
substrate had dissolved. The reaction mixture was then cooled to
0 °C and bromine (7.0 mL, 0.14 mol) in dichloromethane (50
mL) was added drop-wise over a period of 15 min. This solution
was allowed to stir for another 40 min after which time saturated
Na2SO3 (100 mL) was added and the organic layer separated. The
aqueous layer was extracted with dichloromethane (3 × 50 mL)
and the combined organic layers were washed with Na2SO3 (50
mL), water (50 mL), brine (50 mL), and dried over Na2SO4. The
organic layer was filtered and evaporated in vacuo to yield the
title compound 38 (30.3 g, 99%) as a clear oil, which solidified
upon standing and was used without any further purification. Rf =
0.20, (3:1 pentane:EtOAc); 1H NMR (300 MHz; CDCl3) δ = 7.44
(d, 1H, J = 2.2 Hz), 7.23 (m, 1H), (m, 1H), 6.95 (d, 1H, J = 4.1
Hz), 1.28 (s, 9H, -(CH3)3); HRMS (ES-): calculated for
C10H13BrO; 227.0072, found 227.0067.
2-Bromo-4-tert-butyl-6-chlorophenol (39)40
To phenol 38 (30.2 g, 0.132 mol) was added toluene (100 mL)
and diisobutylamine (183 µL, 1.05 mmol). The solution was
heated to 70 °C and at this temperature sulfuryl chloride (10.6

13
2.4 Hz), 6.58 (s, 2H, B(OH)2), 3.94 (s, 3H, (OMe)), 1.32 (s, 9H,
Method 1
ACCEPTED MANUSCRIPT
(CH3)3); 13C NMR (75 MHz; CDCl3) 158.6 (4°), 148.8 (4°),
131.7, 131.1, 126.2 (4°), 61.9 (CH3), 34.5 (4°), 31.2 (CH3)3 (1C
obscured); IR (KBr) νmax 3361, 2956, 1476, 1431, 1398, 1366,
1333, 1236, 1070, 987, 810 and 769 cm-1; HRMS (ES-):
calculated for C11H16BClO3; 241.0803, found 241.0792.
Pd(PPh3)4 (0.12 g, 0.10 mmol) was added to a dry Schlenk
tube containing anhydrous, degassed DMF (25 mL) followed by
aryl chloride 43 (0.64 g, 2 mmol) and the mixture was stirred
under nitrogen for 10 min. Arylboronic acid 32 (0.73 g, 3.0
mmol) was then added as a solid followed by Cs2CO3 (1.34 g, 4.1
mmol). The mixture was then heated to 110 °C overnight (18 h)
after which time it was cooled to room temperature and water (50
mL) and dichloromethane (50 mL) were added. The organic layer
was separated and concentrated in vacuo to give a brown oil
which was re-dissolved in dichloromethane (100 mL), washed
with water (20 mL), brine (20 mL), and then dried over Na2SO4.
The organic solution was filtered and evaporated in vacuo to give
an oil which was purified by column chromatography over silica
gel (10:1 pentane:EtOAc) to yield the title compound 34 (0.48 g,
50%) as a white solid. Rf = 0.60, (3:1 pentane:EtOAc); 1H NMR
(300 MHz; CDCl3) δ = 9.75 (s, 1H, COH), 8.33 (s, 1H, H4), 8.19
(d, 1H, J = 8.6 Hz), 8.09 (d, 1H, J = 8.6 Hz), 8.00 (dd, 1H J1 =
6.3 Hz, J2 = 7.32 Hz), 7.75-7.59 (m, 3H), 7.46-7.38 (m, 5H), 3.70
(s, 3H, OCH3), 1.29 (s, 9H, C(CH3)3); 13C NMR (75 MHz;
CDCl3) 191.5, 156.3 (4°), 151.7 (4°), 149.0 (4°), 148.2 (4°),
143.1 (4°), 136.5 (4°), 136.3 (4°), 134.6 (4°), 132.5 (4°), 130.9,
129.5, 128.9, 128.4 (2C), 128.1, 128.0 (4°), 127.9, 127.6, 127.4,
127.2 (2C), 127.0, 126.9, 122.4, 121.2, 61.2 (OMe), 34.6 (4°),
31.2 (CH3)3; IR (KBr) νmax 1691, 1619, 1322, 770, and 702 cm-1;
HRMS (ES+): calculated for C31H26ClNO2; 480.1730, found
480.1748.
3-(5-tert-Butyl-3-chloro-2-methoxyphenyl)-1-(2-
methylnaphthalen-1-yl)isoquinoline (33)
Pd(PPh3)4 (0.10 g, 86 µmol) was added to a dry Schlenk tube
containing anhydrous, degassed DMF (25 mL) followed by
biaryl 35 (0.88 g, 2.89 mmol) and the mixture was stirred under
nitrogen for 10 min. Boronic acid 32 (0.70 g, 2.9 mmol) was then
added as a solid followed by sodium carbonate (3 mL, 2.0 M).
The mixture was then heated to 110 °C for 2 d after which time it
was cooled to room temperature and water (50 mL) and
dichloromethane (50 mL) were added. The organic layer was
extracted and concentrated in vacuo to give a brown oil which
was re-dissolved in dichloromethane (50 mL), washed with water
(20 mL), brine (20 mL), and then dried over Na2SO4. The organic
solution was filtered and evaporated in vacuo to give an oil
which was purified by column chromatography over silica gel
(1:1 pentane:CH2Cl2) to yield the title compound 33 (0.54 g,
40%) as a white solid. Rf = 0.25, (1:1 CH2Cl2:pentane); m.p. 135-
1
136 °C; H NMR (300 MHz; CDCl3) δ = 8.21 (s, 1H, H4), 7.98-
7.88 (m, 3H), 7.72-7.66 (m, 2H), 7.50 (d, 1H, J = 8.3 Hz), 7.45-
7.36 (m, 4H), 7.25 (app t, 1H, J = 7.9 Hz), 7.15 (d, 1H, J = 8.5
Hz), 3.70 (s, 3H, OCH3), 2.20 (s, 3H, CH3), 1.30 (s, 9H,
C(CH3)3); 13C NMR (75 MHz; CDCl3) 160.1, 151.6, 149.2,
148.0, 136.8, 135.3, 134.9, 134.4, 133.0, 132.1, 130.5, 128.7,
128.4, 127.9, 127.8, 127.52 (2C), 127.48, 127.3, 127.2 (2C),
126.1, 125.8, 124.9, 120.4, 61.3 (OMe), 34.6 (4°), 31.3, (CH3)3,
20.3 (CH3); IR (KBr) νmax 2960, 1618, 1562, 1479, 1320, 1268,
996, 811, and 742 cm-1; HRMS (ES+): calculated for
C31H28ClNO; 466.1938, found 466.1944; C31H28ClNO: calculated
C, 79.90; H, 6.06; N, 3.01, found C, 79.70; H, 6.14; N, 2.98.
Method 2
Pd(PPh3)4 (0.58 g, 0.05 mmol) was added to a dry Schlenk
tube containing anhydrous, degassed DMF (20 mL) followed by
aryl bromide 44 (0.362 g, 1.0 mmol) and the mixture was stirred
under nitrogen for 10 min. Arylboronic acid 32 (0.36 g, 1.5
mmol) was then added as a solid followed by Cs2CO3 (0.49 g, 1.5
o
mmol). The mixture was then heated to 110 C overnight (18 h)
and cooled to room temperature. Water (50 mL) and
dichloromethane (50 mL) were added. The organic layer was
separated and concentrated in vacuo to give a brown oil which
was re-dissolved in dichloromethane (100 mL), washed with
water (20 mL), brine (20 mL), and then dried over Na2SO4. The
organic solution was filtered and evaporated in vacuo to give an
oil which was purified by column chromatography over silica gel
(10:1, pentane:EtOAc) to yield the title compound 34 (0.32 g,
67%) as white solid, identical to a previously prepared sample.
3-(5-tert-Butyl-3-chloro-2-methoxyphenyl)-1-(2-
dibromomethylnaphthalen-1-yl)isoquinoline (41)
To compound 33 (1.50 g, 3.22 mmol) was added N-
bromosuccinimide (1.20 g, 6.75 mmol) and dibenzoyl peroxide
(70%, 0.11 g, 0.32 mmol) followed by CCl4 (125 mL). The
mixture was heated to reflux while being irradiated with a flood
lamp for 7 h after which time N-bromosuccinimide (0.12 g, 0.68
mmol) was added and the mixture allowed to stir at reflux under
irradiation overnight (18 h). The resultant mixture was filtered
and the precipitate washed with benzene (2 × 20 mL). The
mother liquors were combined, washed sequentially with water
(20 mL), NaHCO3 (20 mL), brine (20 mL) and then dried over
CaCl2. The organic layer was filtered and evaporated in vacuo to
yield the title compound 41 (1.98 g, 99%) as a brown solid,
which was used without any further purification. Rf = 0.65, (3:1
Method 3
To compound 41 (3.25 g, 5.21 mmol) was added ethanol (25
mL) and THF (15 mL) and the solution was heated to reflux.
AgNO3 (2.66 g, 15.6 mmol) in water (7.5 mL) was added drop-
wise with stirring to produce a yellow precipitate. When all of the
AgNO3 solution had been added, the reaction was refluxed for a
further 1 h. After this time, the hot mixture was filtered using a
sintered glass funnel and the precipitate washed with more THF
(2 × 20 mL). The mother liquors were combined concentrated
and dichloromethane (100 mL) was added followed by water (30
mL). The organic layer was separated and the aqueous layer
extracted with dichloromethane (2 × 20 mL). The organic layers
were combined, washed with brine (20 mL), dried over Na2SO4,
filtered and evaporated in vacuo to yield the crude product which
was purified by column chromatography over silica gel (10:1
Pentane:EtOAc) to yield the title compound 34 as a white solid
(0.3 g, 12%) which was identical to a previously prepared
sample.
1
pentane:EtOAc); H NMR (300 MHz; CDCl3) δ = 8.43 (s, 1H,
H4), 8.22 (d, 1H, J = 8.8 Hz), 8.11 (d, 1H, J = 8.8 Hz), 8.01 (d,
1H, J = 8.4 Hz), 7.92 (d, 1H, J = 8.0 Hz), 7.85 (d, 1H, J = 2.4
Hz), 7.73 (m, 1 H), 7.51-7.25 (m, 5H), 6.47 (s, 1H), 3.72 (s, 3H,
OCH3), 1.30 (s, 9H, C(CH3)3); 13C NMR (75 MHz; CDCl3)
156.8, 151.6, 148.8, 148.3, 137.5, 136.8, 134.3, 133.6, 131.4,
131.0, 130.2, 128.1, 128.0, 127.8, 127.7 (2C), 27.5, 127.3,
127.21(2C), 127.18(2C), 127.05, 126.2, 121.6, 61.2 (OMe), 39.5
(CHBr2), 34.7 (4°), 31.3 (CH3)3; IR (KBr) νmax 2960, 1561, 1478,
and 750 cm-1; HRMS (ES+): calculated for C31H26Br2ClNO;
622.0148, found 622.0160.
1-[3-(5-tert-Butyl-3-chloro-2-methoxyphenyl)isoquinolin-1-
yl]naphthalene-2-carbaldehyde (34)
1-[3-(5-tert-Butyl-3-chloro-2-hydroxyphenyl)isoquinolin-1-
yl]naphthalene-2-carbaldehyde (47)29

14
Tetrahedron
ACCEPTED MANUSCRIPT
Aldehyde 34 (0.33 g, 0.69 mmol) was placed in a 50 mL
after which time it was placed in ice to cool. An aliquot was
Schlenk tube. HBr (48%, 3 mL) and AcOH (3 mL) were added at
room temperature and the resultant solution heated to 140 °C for
2 h. After this time the solution was cooled to room temperature
and water (10 mL) and dichloromethane (20 mL) were added.
The organic layer was separated and the aqueous layer extracted
with dichloromethane (2 × 10 mL). The combined organic layers
were then washed with brine (20 mL), dried over Na2SO4, filtered
and evaporated in vacuo to give the crude product which was
purified by column chromatography over silica gel (5:1,
pentane:EtOAc) to yield the title compound 47 (215 mg, 67%) as
a pale yellow solid. Rf = 0.30, (5:1 pentane:EtOAc); m.p. 200-
202 °C; 1H NMR (300 MHz; CDCl3) δ = 9.68 (s, 1H, COH), 8.45
(s, 1H, H4), 8.13-8.09 (m, 3H), 8.00 (d, 1H, J = 8.1 Hz), 7.95 (d,
1H J = 2.3 Hz), 7.77 (m, 1H), 7.62 (dd, 1H, J1 = 7.3 Hz, J2 = 14.5
Hz), 7.45-7.34 (m, 4H), 7.22 (d, 1H, J = 8.5 Hz), 1.41 (s, 9H,
C(CH3)3); 13C NMR (75 MHz; CDCl3) 190.6, 154.7 (4°), 152.6
(4°), 150.4 (4°), 142.3 (4°), 140.5 (4°), 137.2 (4°), 136.3 (4°),
132.3 (4°), 132.2 (4°), 132.0, 130.2, 129.3, 128.9, 128.6, 128.5,
128.1 (4°), 127.9, 127.8, 127.2, 126.9, 122.8, 122.7 (4°), 121.4,
119.7 (4°), 116.3, 34.5 (4°), 31.6 -(CH3)3; IR (KBr) νmax 3452,
2954, 1695, 1620, 1587, 1561, 1462, 1256, and 743 cm-1; HRMS
(ES+): calculated for C30H24ClNO2; 466.1574, found 466.1587.
injected into the HPLC in order to determine the change in
enantiomeric excess. This process was repeated at intervals of 30
min and a graph of ln (ee0/ee) vs. time was plotted. This entire
process was repeated at three other temperatures and the rate of
racemisation at these temperatures was calculated. These rates
were subsequently used to draw Arrhenius and Eyring plots from
which the kinetic parameters for racemization were obtained.
General Procedure for the diethylzinc addition to aldehydes
Method A
To a solution of 30 (7 mg, 15 µmol) in toluene (1 mL) at room
temperature was added ZnEt2 (0.6 mL, 1 M in hexane, 0.6 mmol)
and the solution was stirred for 30 min. After this time the
solution was cooled to 0 °C and benzaldehyde (30 µL, 0.3 mmol)
was added. The reaction was stirred for a further 48 h at 0 °C
after which time 5% HCl (5 mL) and diethyl ether (20 mL) were
added and the organic layer was separated. The aqueous layer
was extracted with diethyl ether (2 × 5 mL) and the organic
layers were combined, washed with brine (10 mL), dried over
MgSO4, filtered and concentrated in vacuo to yield the crude
product which was purified by column chromatography over
silica gel (5:1 pentane/EtOAc) to give the pure alcohol.
4-tert-Butyl-2-chloro-6-[1-(2-hydroxymethylnaphthalen-1-
yl)isoquinolin-3-yl]-phenol (30)
Method B
To ligand 30 (40 mg, 85 mmol) was added toluene (4 mL) and
the solution stirred at room temperature for 5 min. After this time
300 µL of this stock solution (3 mg, 6 µmol, 1 mol %) was
transferred to a Schlenk tube and a further 1 mL of toluene
added. To this solution at room temperature was added ZnEt2
(1.2 mL, 1 M solution in hexane, 1.2 mmol) and the solution
stirred for 30 min. After this time, the solution was cooled to -20
°C and benzaldehyde (58 µL, 0.6 mmol) was added. The reaction
was stirred for a further 48 h at 0 °C, after which time 5% HCl (5
mL) and diethyl ether (20 mL) were added and the organic layer
was separated. The aqueous layer was extracted with diethyl
ether (2 × 5 mL) and the organic layers were combined, washed
with brine (10 mL), dried over MgSO4, filtered and concentrated
in vacuo to yield the crude product which was purified by
column chromatography over silica gel (5:1, pentane/EtOAc) to
give the pure product.
Aldehyde 47 (0.10 g, 0.22 mmol) was placed in a 25 mL
round-bottomed flask to which THF (3 mL) and ethanol (3 mL)
were added. The solution was allowed to stir at room temperature
and (11.8 mg, 0.31 mmol) in water (220 µL) was added drop-
wise and the mixture was allowed to stir for a further 1 h. Water
(5 mL) was added, followed by 10% HCl (5 mL) and
dichloromethane (50 mL). The organic layer was separated and
the aqueous layer was extracted with dichloromethane (2 x 20
mL). The combined organic extracts were then washed with brine
(20 mL), dried over Na2SO4, filtered and evaporated in vacuo to
yield the crude product which was purified by column
chromatography over silica gel (5:1, pentane:EtOAc) to yield the
title compound 30 (90 mg, 92%) as a yellow solid. Racemic 30
was resolved via semi-preparative HPLC using a CHIRALPAK
AD column to yield both (-)-30 and (+)-30 in >99% ee. Rf =
1
0.40, (2:1 CH2Cl2:pentane); m.p. 205-207 °C; H NMR (300
MHz; CDCl3) δ = 8.37 (s, 1H, H4), 8.08-8.04 (m, 2H), 7.95-7.93
(m, 2H), 7.82-7.72 (m, 2H), 7.49-7.37 (m, 4H), 7.26 (ddd, 1H, J1
= 1.2 Hz, J2 = 6.9 Hz, J3 = 9.6 Hz), 7.45-7.34 (m, 4H), 7.22 (d,
1H, J = 8.5 Hz), 7.00 (d, 1H, J = 8.57 Hz), 4.49 (d, 1H, J = 13.0
Hz), 4.38 (d, 1H, J = 13.0 Hz) 1.41 (s, 9H, C(CH3)3); 13C NMR
(75 MHz; CDCl3) 156.8 (4°), 152.7 (4°), 150.3 (4°), 142.0 (4°),
137.4 (4°), 137.2 (4°), 132.9 (4°), 132.5 (4°), 132.2 (4°), 131.8,
129.7, 128.7, 128.2, 128.1, 127.6, 127.5, 127.2 (4°), 126.9, 126.1,
125.7, 125.6, 122.6 (4°), 121.2, 119.8 (4°), 115.6, 63.00 (CH2),
34.4 (4°), 31.5 (CH3)3; HPLC AD semi-preparative column, 4.7
ml/min, 95:05 Pentane:IPA, 40 °C, tR(-)-30 = 27.9 min, tR(+)-30
= 37.1 min; αD = +26.0, -30.0 (CHCl3, c=1.0); IR (KBr) νmax
3444, 2948, 1497, 1278, and 757 cm-1; HRMS (ES+) calculated
for C30H24ClNO2; 468.1730, found 468.1712; C30H24ClNO2:
calculated C, 76.99; H, 5.60; N, 2.99, found C, 76.76; H, 5.66; N,
2.91.
Acknowledgments
Financial support from Enterprise Ireland and the Centre for
Synthesis and Chemical Biology (CSCB), which is funded under
the Programme for Research in Third-Level Institutions (PRTLI)
administered by the Higher Education Authority (HEA) is
gratefully acknowledged. We would also like to thank Dr
Tomasz Fekner of this research group for helpful discussions
during this research and the preparation of this manuscript.
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