Resolution and coupling of 1-(2′-hydroxy-1′-naphthyl)isoquinolines

Article abstract of DOI:10.1016/S0040-4020(01)00064-3

The synthesis of bridged dimeric isoquinolylnaphthols has been developed. A simple method for the resolution of 1,1′-isoquinolyl-2′-naphthol permits measurement of the optical stability of the monomer, and in several cases slow racemisation at ambient temperature was observed. The enantiomeric stability is not greatly affected by steric buttressing. An unusual enhancement of the rate of atropisomerism is provided by the 3-bromomethylisoquinolines, and undermines the possibility of coupling pure enantiomeric components to provide a single stereoisomer of a tetradentate ligand.

Full text of DOI:10.1016/S0040-4020(01)00064-3

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2545±2554
Resolution and coupling of
1-(20-hydroxy-10-naphthyl)isoquinolines
Sonia C. Tucker,a John M. Brown,a,p John Oakesb and David Thornthwaiteb
aDyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, UK
bUnilever Research Laboratory, Bebington, Wirral L63 3JW, UK
In appreciation of the inventive contributions of Henri Kagan to asymmetric catalysis
Received 25 July 2000; revised 12 October 2000; accepted 16 October 2000
AbstractÐThe synthesis of bridged dimeric isoquinolylnaphthols has been developed. A simple method for the resolution of 1,10-iso-
quinolyl-20-naphthol permits measurement of the optical stability of the monomer, and in several cases slow racemisation at ambient
temperature was observed. The enantiomeric stability is not greatly affected by steric buttressing. An unusual enhancement of the rate of
atropisomerism is provided by the 3-bromomethylisoquinolines, and undermines the possibility of coupling pure enantiomeric components
to provide a single stereoisomer of a tetradentate ligand. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
There exists extensive literature on transition metal
complexes of the tetradentate Schiff base ligand N,N0-dis-
alicylidene-1,2-diaminoethane 1 and various derivatives.1
These Salen ligands have recently been the focus of
renewed attention as a result of their successful application
in various catalytic processes. Particularly prominent has
been the emergence of `Jacobsen epoxidation' using chiral
manganese Salen catalyst 2, which constitutes a practical,
reliable method for achieving highly enantioselective epoxi-
dations of several classes of ole®n.2 Modi®cations to the
basic ligand structure have enabled advances to be made
in various other catalytic asymmetric processes such as sulf-
oxidation or sul®midation,3 cycloadditions,4 cyanohydrin
formation,5 cyclopropanation,6 aziridination,7 C±H oxi-
dative activation,8 and in the desymmetrisation or kinetic
The strategy adopted involved various rational modi®-
resolution of epoxides.9 We became interested in the syn-
cations to the simple unit 3, which led ultimately to struc-
tures 4 and 5. Two main issues were addressed:
thesis of stereochemically de®ned polydentate ligands
comprising naphthol-isoquinoline donor sets exempli®ed
by the simple unit 1-(20-hydroxy-10-naphthyl)isoquinoline
3. These ligands offer a coordinating environment related to
the one present in the Salen ligands, but with chirality that
stems from restricted rotation about the biaryl axis, rather
than from central asymmetry in a diamine bridge.
1. The introduction of a suitable substituent at C3 of the
isoquinoline, thereby opening up a route to a potentially
tetradentate ligand by bridged dimer formation.
2. Bridging two racemic biaryls would lead to complexity
in the product as both an (RpRp) racemic pair and an
(RpSp) meso-diastereomer could be produced. The logical
step, therefore, was to resolve the biaryl moiety before
bridging. Biaryl 3 was anticipated to be optically labile at
room temperature and the possible requirement for the
introduction of substituents that would block the racemi-
sation pathway was foreseen. The effect of such substi-
tution was found to be unpredictable, and forms the basis
for much of this work.
Keywords: racemisation; enantiomers; palladocycles; isoquinolines; atrop-
isomerism.
p
Corresponding author. Tel.: 144-1865-275642; fax: 144-1865-275674;
e-mail: bjm@ermine.ox.ac.uk
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00064-3

2546
S. C. Tucker et al. / Tetrahedron 57 (2001) 2545±2554
Scheme 1. Synthetic route to compound 1.
By treatment of 3 with one equivalent of (1)-tartaric acid,
recrystallisation from acetone and subsequent treatment
with ammonia to liberate scalemic 3 it was evident from
polarimetry that the parent biaryl was prone to racemisation
at ambient temperature. It was thought that the introduction
0
of a tert-butyl group at C3 would buttress the hydroxyl
group, thereby increasing its interaction with H8 and raising
the energy barrier to biaryl rotation suf®ciently so as to halt
racemisation (Scheme 2).
Synthesis of 13, the 3,6-di-tert-butylated analogue of 3 has
been published previously (Scheme 3).11 tert-Butyl groups
were introduced into b-naphthol by Friedel-Crafts
reaction to give 8 which was protected as its methyl ether
9. Thereafter the synthesis parallels that of 3 but with
reduced yields owing to the buttressing effect of the
0
bulky tert-butyl group at C3 . An improved synthesis of
the 1-bromo-substituted ether 10 was developed which
allowed the reaction to be performed on a large scale with-
out the need for a dif®cult chromatographic separation. The
derived boronic acid 11 was then coupled to 6 under
standard Suzuki conditions. Use of caesium carbonate as
base had a marked effect on the yield of this reaction. The
coupled product 12 was obtained in 64% yield compared to
the 30% previously reported when potassium carbonate was
used.
2. Results and discussion
2.1. Synthesis of precursors
Biaryl 3 was readily available on a large scale according to a
previously published route in which the key step involved
a Suzuki coupling reaction between isoquinoline 6 and
boronic acid 7 (Scheme 1).10
Scheme 2. Analysis of the racemisation pathways for the series of biaryls.

S. C. Tucker et al. / Tetrahedron 57 (2001) 2545±2554
2547
Scheme 3. Synthetic route to compound 13.
Scheme 4. The resolution protocol for racemic 3 and 13.
2.2. Resolution procedure
under ambient conditions. Values of kracˆ2.77£1027 s21
for 3 and kracˆ9.55£1027 s21 for tert-butylated analogue
13, were obtained, corresponding to half-lives of ca. 700
and 200 h, respectively. It was immediately apparent that
A direct comparison between the optical stabilities of 3 and
13 could be made using chloro-bridged palladium dimer 14
as a resolving agent (Scheme 4).12 Although this method-
ology has been extensively used for the resolutions of
diphosphines, phosphinamines and more occasionally for
other chelating reactants including amino-acids,13 it has
not previously been employed in aminoalcohol resolution.
When a CDCl3 solution of 3 was treated with 0.5 equiv. of
0
the introduction of a bulky group at C3 did not have the
desired effect of preventing racemisation. Indeed, the rate of
racemisation was increased by an approximate factor of
four. As in the parent series, where 1-(10-naphthyl)isoquino-
line is far more stereochemically labile than 1,10-
binaphthyl,14 the racemisation rates are high. For com-
parison, 2-hydroxy-1,10-binaphthyl racemises in benzene
solution with a half-life of about two days.15
1
Pd-dimer the H NMR of the resulting solution indicated
conversion to two diastereomers, (R,R)-15a and (R,S)-15a
in comparable amounts. Repeating the experiment using
0.25 equiv. of dimer led to selectivity in the formation of
the two diastereomers (87:13). The uncomplexed ligand was
recovered by crystallisation and the speci®c rotation of a
sample dissolved in chloroform was observed over a period
of time. A similar procedure was followed with biaryl 13. In
this latter case, it was possible to recover the free ligand by
column chromatography, and also to isolate the major
palladium diastereomer of 15b, which was characterised
2.3. Synthesis of bis-biaryls
0
The unpredicted result that substitution at C3 increased the
rate of racemisation (vide infra) prompted questions about
the consequence of introducing substituents at C3 of the
isoquinoline, necessary for the construction of a bridge
between two biaryls. The achievement of a route to a bis-
biaryl where the two biaryl units are linked by a CH2±S±
CH2 bridge provided a situation where the effect of such
substitution on racemisation could be followed by 1H
NMR. Two such ligands were synthesised as shown in
Scheme 5.
1
by H, 13C NMR and electrospray MS. Fig. 1 shows the
decline of speci®c rotation with time ®tted to an exponential
decay for the two biaryls. Thus it was possible to derive
half-lives and rate constants for the racemisation process

2548
S. C. Tucker et al. / Tetrahedron 57 (2001) 2545±2554
2-Carbomethoxybenzaldehyde 16 was condensed with
hippuric acid to give oxazolone 17 according to a literature
procedure.16 Cyclisation with KOH in MeOH gave substi-
tuted isocarbostyril 18,17 which on treatment with POCl3
underwent both chlorination and aromatisation to give the
required substituted isoquinoline 19. The product was sepa-
rately coupled to boronic acids 7 and 11 under Suzuki con-
ditions. With the unhindered boronic acid 7 the coupling
was carried out using Pd(PPh3)4 as catalyst and aq. K2CO3
as base, and gave biaryl 20 in 88% yield. Under these con-
ditions the ester functionality was hydrolysed but could be
readily converted into ester 21 on treatment with methyl
iodide. As expected, the coupling with tert-butylated
boronic acid 11 was initially more dif®cult to achieve. Opti-
misation of the reaction conditions, particularly in the
choice of the palladium phosphine ligands, allowed the
reaction to be performed on a large scale with satisfactory
yields. Use of
a Pd2dba3´CHCl3/tri-2-furylphosphine
catalyst system18 gave biaryl 24 in 75% (as determined by
1H NMR), a notable improvement on the 19% yield
obtained with Pd(Ph3)4 as catalyst. Triphenylarsine was
also an effective palladium ligand; in this case a yield of
59% was achieved. It was also found convenient to use the
base, K2CO3, as a ®ne suspension in DME.
Methyl esters 21 and 24 were reduced in turn to alcohols 22
and 25. Under demethylation conditions the bromides 23
and 26 were formed in good yield. Reaction of 26 with
Figure 1. Decline in speci®c rotation with time for compounds 3 and 13 at
258C in CHCl3 measured by polarimetry.
Scheme 5. Coupling routes to compounds 4 and 5 via biaryl precursors

S. C. Tucker et al. / Tetrahedron 57 (2001) 2545±2554
2549
pair and the meso (R,S) diastereomer. This was con®rmed by
1H NMR which showed nine distinct resonances for the
aromatic protons and two doublets for the CH2 protons in
each case.
The related non tert-butylated compound 4 was also
prepared. The two diastereomers were easily distinguish-
able by their CH2 peaks; one appears as a very distinct
AB quartet centred at 4.12 ppm, the other as two coalesced
doublets at 4.00 ppm. These diastereomers could not be
separated by chromatography, although recrystallisation
from ethyl acetate gave a diastereomeric mixture with a
d.e. of 54%.
For both 4 and 5 interconversion between the diastereomers
could be observed by recording at intervals the H NMR
1
spectra of samples with an initial diastereomeric excess. The
results are displayed graphically in Fig. 2. A fairly slow loss
of d.e. is indicated for both compounds. The accuracy of the
half-lives obtained from the graphs (t1/2ˆ300 h for 4 and
370 h for 5) is limited by the method of determining d.e.
1
from relative integrals in the H NMR spectrum, but it is
clear that both compounds stereomutate with half lives of
the same order of magnitude as one another, and similar to
those derived for the racemisation of the simple monomer
ligands 3 and 13. This is in marked contrast to the situation
that exists for the bromide precursors 23 and 26 to be
discussed in the following section.
Figure 2. Interconversion of diastereomers of compounds 4 and 5 in CDCl3
at 258C.
0.5 equiv. of sodium sulphide in DMF resulted in complete
conversion to two major products. These were separated by
column chromatography and shown to have identical
masses corresponding to that expected for the sulphur
bridged dimer 5, and were thus assigned as the (R,R)/(S,S)
2.4. Anomalous behaviour of bromides 23 and 26
Resolution experiments similar to those described
previously were carried out on biaryls 23 and 26. The
complexation step was shown by 1H NMR to proceed
quite slowly in either case, compared to biaryls 3 and 13,
and so reactions were stirred overnight prior to recovery of
the free ligand. With the tert-butylated biaryl 26 only one
diastereomer was seen after stirring for 24 h. The uncom-
plexed ligand was separated by column chromatography
and further elution of the column afforded the palladium
complex, albeit of the other hand. The decline in speci®c
rotation of the recovered biaryl was followed and the
rapidity with which this occurred (t1/2ˆ160 min) was quite
startling (Fig. 3). This result was reproducible, and the
stereochemical lability of 26 further demonstrated by the
observation that if a slight excess of resolving agent was
used complete conversion of the racemate to a single palla-
dium diastereomer occurred, identical to the one previously
observed. The dramatic effect that the CH2Br substituent
exerted on the rate of racemisation led to the expectation
that biaryl 23 would also racemise at a much higher rate than
its non C3-substituted analogue. However, when the experi-
ment in question was carried out the opposite result was
obtained. The racemisation rate of the uncomplexed ligand
was very slow; indeed a decline in speci®c rotation could
only be observed in larger scale assays. The prolonged
period of observation required rendered the results less
reliable than for the other three biaryls, but a half-life of
the order of a year at ambient temperature could be
extrapolated from the data (Fig. 3). The results in this case
were slightly complicated by the presence (ca. 5%) in the
recovered material of what was identi®ed as the chloro-
substituted biaryl 27. A peak of the correct mass was seen
Figure 3. Decline in speci®c rotation with time for compounds 23 and 26 at
258C in CHCl3 measured by polarimetry.

2550
S. C. Tucker et al. / Tetrahedron 57 (2001) 2545±2554
Scheme 6. A possible pathway for the easy racemisation of the bromomethyl compound 26.
in the mass spectrum and the 1H NMR showed two doublets
in the methylene region, very close to the doublets assigned
to the bromo-substituted compound. Thus the decline in
optical rotation could not be attributed entirely to racemi-
sation of 23.
The increase in the rate of racemisation on going to 13 was,
therefore, initially surprising. However, inspection of the
literature revealed several precedents whereby bulky sub-
stituents on biaryls apparently facilitated racemisation.
Some years ago a series of papers was published dealing
with the unexpectedly facile racemisation of several 8,80
disubstituted binaphthyls19 and more recently Fuji and
co-workers reported on the optical liability of 8-diphenyl-
phosphinoyl-80-methoxy-1,10-binaphthyl as compared to
the enantiomerically stable 2,20 substituted analogue.20
Meyers and co-workers have observed the easy racemi-
sation of an 8,80-disubstituted-bis-oxazolinylbinaphthyl.21
In both of the recent cases unfavourable ground-state effects
were invoked to explain the easy rotation about the axial
biaryl bond; in the ®rst case due to steric destabilisations
and in the second to lone pair repulsion operating speci®c-
ally in one diastereomer. A related argument could in prin-
ciple apply to biaryls 3 and 13. Crystal structures of bulky
di-ortho-substituted aromatic rings have been recorded, and
the bonds to the substituents shown to be both splayed out in
the main arene plane and also displaced from it.22 In order to
test this view, preliminary molecular modelling on was
carried out and a conformational search for the global
energy minima revealed various small but signi®cant differ-
ences in bond angles between the biaryls that could lead to
destabilisation of the ground state. However, the size of the
effect for the tert-butylated bromide 26 would indicate that
other more important factors are involved. The inferred
rapid rotation about the biaryl axis during the course of
the coupling reaction with Na2S points towards pH
dependence and/or solvent interactions as playing a role.
The intervention of a cyclised intermediate like 28 is
sheer speculation at this stage, but would account for
the enhanced rapidity of racemisation observed with
an adjacent tert-butyl substituent at the 30-position23
(Scheme 6).
With the high stability of bromide 26 to racemisation estab-
lished and the procedure for its conversion, under very mild
conditions, to a tetradentate ligand already in place the
synthesis of a single stereoisomer seemed possible. Accord-
ingly a sample of resolved ligand 26 was stirred for 1 h in
DMF with 0.5 equiv. of sodium sulphide. The usual work-
up procedure (removal of DMF in vacuo, followed by
column chromatography) was used. Most surprisingly two
diastereomers in equal proportions were observed in the 1H
NMR. The reaction was repeated on an NMR scale in d7
DMF. This showed that conversion to products was very
fast. No starting material was seen by the time the acqui-
sition was complete and two diastereomers were indicated
in the product. The optical stability of 23 in DMF was
con®rmed by polarimetry, as was the stability of product 4
towards the interconversion of its diastereomers. These
observations indicated that the loss of stereochemical integ-
rity in the product was associated with the course of the
substitution reaction.
2.5. Discussion of racemisation experiments
The two possible racemisation pathways for a biaryl are
depicted in Scheme 2, with the planar transition state
shown for each case. In the trans pathway the biggest inter-
actions as the two arms pass each other are between H8 and
the hydroxy group. In the cispathway the passing position
0
results in severe interactions between H8 and H8 . Despite
the potential for stabilisation by hydrogen bonding in this
case, such unfavourable interactions were thought to effec-
tively preclude this pathway from contributing to the
racemisation process. In the discussion that follows the
trans pathway will be assumed.
3. Experimental
3.1. General methods
The rationale behind the introduction of the tert-butyl
0
groups in 3 was that a bulky substituent at C3 would distort
Reactions involving air-sensitive reagents were conducted
under a dry argon atmosphere, using standard vacuum line
techniques in Schlenk glassware. Melting points were
recorded on a Reichert±Kof¯er block and are uncorrected.
Elemental microanalyses were performed using a Carlo
Erba 1106 elemental analyser. Speci®c rotations were
recorded on a thermostatically controlled Perkin±Elmer
241 polarimeter with a path length of 1 dm, using the
589.3 nm D-line of sodium. Infrared spectra were recorded
the C±O bond of the hydroxyl group and suf®ciently
increase the crowding in the transition state so as to prevent
racemisation. That the tert-butyl group exerted such a
buttressing effect on the hydroxyl group was evident from
a number of prior observations. For example, the reversible
bromination of the tert-butylated methoxynaphthol 9 and
the instability of the subsequently derived boronic acid 11
0
both indicated destabilisation of C1 .
11

S. C. Tucker et al. / Tetrahedron 57 (2001) 2545±2554
2551
on a Perkin±Elmer 1750 Fourier Transform spectrometer.
Samples were prepared as thin ®lms on NaCl plates or as
KCl discs. 1H NMR spectra were recorded on Varian
Gemini 200 (200 ), Bruker AM 250 (250 MHz), Bruker
WH 300 (300 MHz), Bruker AMX 500 (500 MHz), or
Bruker AM 500 (500 MHz) spectrometers. Mass spectra
were recorded on a Trio 1, a Hewlett Packard series 1050
(atmospheric pressure chemical ionisation), ZAB1F or BIO-
Q spectrometer. High-resolution mass spectra (HRMS)
were run on a V.G. Autospec spectrometer operating in
positive electrospray mode.
DME (10 ml) was added to Pd2(dba)3´CHCl3 (373 mg,
0.360 mol) and tri-2-furylphosphine (334 mg, 1.44 mmol),
and stirred for 10 min under an argon atmosphere. The
bright yellow solution was transferred via cannula to a
Schlenk containing 11 (2.20 g, 7.00 mmol), 19 (1.55 g,
7.00 mmol) and powdered potassium carbonate (1.90 g,
14 mmol), and heated at 1008C for 24 h. The mixture was
then cooled and the solvent evaporated. The residue was
taken into diethyl ether (200 ml) and ®ltered. The solid
residue was washed with more diethyl ether and evaporated
to leave a brown oil which was stirred overnight with 2 M
sodium hydroxide (50 ml), thus hydrolysing unreacted 19.
The desired product was extracted with diethyl ether
(2£25 ml), dried (MgSO4), ®ltered and the solvent evapo-
rated to give a yellow oil. Puri®cation by ¯ash chroma-
tography on silica gel (dichloromethane, Rfˆ0.21) gave
the title compound as a white crystalline solid (1.79 g,
56%) mp 1118C (Found: C, 78.99; H, 7.39; N, 3.03.
C30H33NO requires C, 79.09; H, 7.30; N, 3.07%); dH
(500 MHz; CDCl3) 8.73 (1H, s, H4), 8.06 (1H, d, Jˆ
3.1.1. Preparation of 1-bromo-3,6-di-tert-butyl-2-meth-
oxynaphthalene 10.
A solution of bromine (11.6 ,
73.0 mmol) in chloroform (50 ml) was placed in a pres-
sure-equalising addition funnel, and added over a period
of 5 min to a stirred ice cold solution of 9 (19.6 g,
73.0 mmol) in chloroform (300 ml). The reaction mixture
was basi®ed by addition of 2 M sodium hydroxide (1 l) with
vigorous stirring, then the organic layer separated, and the
solvent evaporated to give a yellow oil. Crystallisation from
methanol gave the title compound as white needles (19.7 g,
60%), data as Ref. 7.
0
0
8.2 Hz, H5), 7.91 (1H, s, H4 ), 7.78 (1H, d, Jˆ2.0 Hz, H5 ),
7.76 (1H, ddd, Jˆ8.2, 6.7, 0.9 Hz, H6), 7.64 (1H, d, Jˆ
8.4 Hz, H8), 7.55 (1H, ddd, Jˆ8.3, 6.7, 1.0 Hz, H7), 7.34
0
0
(1H, dd, Jˆ8.9, 2.0 Hz, H7 ), 7.10 (1H, d, Jˆ8.9 Hz, H8 ),
4.05 (3H, s, CO2CH3), 3.22 (3H, s, OCH3), 1.54 (9H, s,
t-butyl), 1.37 (9H, s, t-butyl); dC (125.8 MHz; CDCl3)
166.7, 159.4 156.4, 147.3, 142.2, 141.1, 136.0, 131.1,
130.8, 130.4, 129.9, 129.7, 128.2, 127.8, 127.0, 126.0,
125.0, 123.9, 123.7, 122.8, 62.0, 52.9, 35.4, 34.6, 31.2,
30.7; m/z (APCI1; NH3); 456 (M11, 100%).
3.1.2. Preparation of 3-carbomethoxyisocarbostyril 18.
Compound 17 as in Ref. 14; bright yellow powder (58.1 g,
61%) mp 165±1688C (lit.14 1718C); dH (300 MHz; CDCl3)
8.65 (1H, d, Jˆ8.6 Hz), 8.20±8.15 (3H, m), 8.02 (1H, d,
Jˆ8.5 Hz), 7.70±7.45 (5H, m), 3.95 (3H, s); dC (50.3 MHz;
CDCl3) 167.6, 164.5, 134.8, 133.9, 133.8, 133.1, 132.2,
131.6, 131.0, 130.3, 129.7, 129.2, 128.7, 125.5, 52.5; m/z
(APCI1; NH3) 308 (M11, 60%). From 9.18 g 17 pro-
ceeding as Ref. 1515: white needles of compound 18
(4.98 g, 79%) mp 163±1658C (lit.15 161±1628C) (Found:
C, 64.94; H, 4.37; N, 6.91. C11H9NO3 requires C, 65.02;
H, 4.46; N, 6.89%); dH (300 MHz; CDCl3) 9.24 (1H, br s,
NH), 8.46 (1H, d, Jˆ7.9 Hz, H8), 7.77±7.60 (3H, m, H5, H6,
H7), 7.38 (1H, s, H4), 3.99 (3H, s, OCH3); dC (125.8 MHz;
CDCl3) 162.5 162.4, 136.1, 133.2, 132.2, 129.5, 128.4,
128.0, 111.5, 53.1; m/z (NH3; APCI1) 204 (M11, 100%).
3.1.5. Preparation of 1-(3,6-di-tert-butyl-2-methoxy-1-
naphthyl)-3-hydroxymethylisoquinoline 25. 24 (2.19 g,
4.81 mmol) was dissolved in dry THF (20 ml) and a suspen-
sion of lithium borohydride (209 mg, 9.62 mmol) in THF
(40 ml) added. The mixture was stirred at room temperature
overnight, then quenched by addition of water (20 ml) and
1 M hydrochloric acid (15 ml). The solvent was evaporated
and the product extracted into dichloromethane (30 ml),
washed with water (2£20 ml), dried (MgSO4), ®ltered and
concentrated. The residue was triturated with pentane
(20 ml) to give the title compound as a pale yellow solid
(1.89 g, 92%) mp 146±1488C; dH (500 MHz; CDCl3) 7.94
(1H, s, H4), 7.93 (1H, d, Jˆ8.2 Hz, H5), 7.80 (1H, d, Jˆ
3.1.3. Preparation of 3-carbomethoxy-1-chloroisoquino-
line 19. Phosphoryl chloride (20.0 ml, 21.5 mol) was added
to 18 (2.35 g, 21.5 mol), and the resulting white suspension
brought to re¯ux. Dissolution occurred and the pale yellow
solution was stirred at re¯ux for a further 1.5 h. After
cooling to room temperature the solution was poured
slowly, with external cooling, into a 2 l beaker containing
water (100 ml). A white precipitate was formed and heat
and HCl gas evolved. The mixture was neutralised by care-
ful addition of 2 M sodium hydroxide (600 ml) and the
product extracted with diethyl ether (3£200 ml). The
combined organics were dried (MgSO4), ®ltered and the
solvent evaporated to give the title compound as a white
solid (4 g, 84%) mp 118±1198C (Found: C, 59.23; H, 3.8;
N, 6.16. C11H8O2NCl requires C, 59.61; H, 3.64; N, 6.32%);
dH (300 MHz; CDCl3) 8.54 (1H, s), 8.43±8.40 (1H, m),
8.02±7.81 (3H, m), 4.05 (3H, s); dC (50.3 MHz; CDCl3)
165.3, 152.0, 140.4, 137.3, 132.2, 131.0, 128.7, 128.4,
126.8, 124.3, 53.0; m/z (APCI1; NH3) 222 (M11, 100%).
0
0
2.0 Hz, H5 ), 7.79 (1H, s, H4 ), 7.44 (1H, dd, Jˆ8.3, 7.9 Hz,
H6), 7.59 (1H, d, Jˆ8.3 Hz, H8), 7.35 (1H, dd, Jˆ8.3,
0
7.9 Hz, H7), 7.34 (1H, dd, Jˆ8.9, 2.0 Hz, H7 ), 7.07 (1H,
0
d, Jˆ8.9 Hz, H8 ), 5.05 (1H, d, Jˆ13.9 Hz, OCH2), 5.02
(1H, d, Jˆ13.9 Hz, OCH2), 3.19 (3H, s, OCH3), 1.54 (9H,
s, t-butyl), 1.37 (9H, s, t-butyl); dC (125.8 MHz; CDCl3)
158.2, 156.7, 151.4, 147.5, 142.3, 137.2, 131.2, 130.6,
130.2, 127.8, 127.5, 127.2, 126.8, 125.1, 123.8, 123.0,
116.8; m/z (APCI1; NH3) 428 (M11, 100%), HRMS,
428.2591; Calcd 428.2590.
3.1.6. Preparation of 3-bromomethyl-1-(3,6-di-tert-
butyl-2-hydroxy-1-naphthyl)isoquinoline 26. Compound
25 (250 mg, 0.585 mmol) was dissolved in dry dichloro-
methane (10 ml) and stirred overnight with boron tri-
bromide (0.11 ml, 1.2 mmol). Water (10 ml) was added to
quench the reaction, then 1 M sodium hydroxide (15 ml)
and the mixture stirred for 4 h. More dichloromethane
(10 ml) was added and the organic layer was separated,
3.1.4. Preparation of 1-(3,6-di-tert-butyl-2-methoxy-1-
naphthyl)-3-carbomethoxyisoquinoline 24. Dry degassed

2552
S. C. Tucker et al. / Tetrahedron 57 (2001) 2545±2554
dried (MgSO4), ®ltered and evaporated to give a solid.
Puri®cation by column chromatography on silica gel
(dichloromethane, Rfˆ0.7) gave the title compound as a
yellow crystalline solid (226 mg, 81%) mp 109±1108C
(Found: C, 70.01; H, 6.19; N, 2.81. C28H30BrNO requires
C, 70.58; H, 6.35; N, 2.94%); dH (500 MHz; CDCl3) 8.82
(1H, br s, OH), 7.92 (1H, d, Jˆ8.3 Hz, H5), 7.88 (1H, s, H4),
precipitate isolated by suction ®ltration and dried in a
dessicator over phosphorous pentoxide to yield the title
compound as a pale yellow powder (18.0 g, 88%) mp
165±1678C; dH (500 MHz; DMSO) 8.76 (1H, s, H4), 8.31
0
(1H, d, Jˆ8.2 Hz, H5), 8.21 (1H, d, Jˆ9.1 Hz, H4 ), 8.02
0
(1H, d, Jˆ8.1 Hz, H5 ), 7.88 (1H, dd, Jˆ8.2, 7.4 Hz, H6),
0
7.69 (1H, d, Jˆ9.1 Hz, H3 ), 7.65 (1H, dd, Jˆ8.4, 7.4 Hz,
0
0
7.86 (1H, s, H4 ), 7.77 (1H, d, Jˆ1.9 Hz, H5 ), 7.72 (1H, dd,
H7), 7.44 (1H, d, Jˆ8.4 Hz, H8), 7.38 (1H, dd, Jˆ8.1,
0
0
Jˆ8.3, 7.2 Hz, H6), 7.62 (1H, d, Jˆ8.5 Hz, H8), 7.41 (1H,
7.9 Hz, H7 ), 7.10 (1H, d, Jˆ8.1 Hz, H8 ), 3.76 (3H, s,
OCH3); dC (125.8 MHz; DMSO) 166.8, 157.9, 154.6,
141.8, 135.8, 133.2, 131.3, 130.8, 130.1, 129.5, 128.8,
128.6, 128.2, 127.1, 126.7, 124.3, 123.8, 123.3, 120.6,
113.9, 56.4;
0
dd, Jˆ8.5, 7.2 Hz, H7), 7.25 (1H, dd, Jˆ8.9, 1.9 Hz, H7 ),
0
6.99 (1H, d, Jˆ8.9 Hz, H8 ), 4.89 (1H, d, Jˆ10.3 Hz,
CH2Br), 4.78 (1H, d, Jˆ10.3 Hz, CH2Br), 1.58 (9H, s,
t-butyl), 1.39 (9H, s, t-butyl); dC (125.8 MHz; CDCl3)
158.8, 153.0, 148.8, 145.8, 139.2, 137.7, 131.2, 129.5,
128.8, 128.2, 127.8, 127.6, 127.5, 127.2, 124.6, 124.2,
123.2, 119.7, 116.5, 35.5, 34.5, 34.3, 31.3, 29.9; m/z
(APCI1; NH3) 477 (M11, 85%).
3.1.11. Preparation of 3-carbomethoxy-1-(2-methoxy-1-
naphthyl)isoquinoline 21. 20 (8.46 g, 25.7 mmol) was
re¯uxed overnight with potassium carbonate (14.2 g,
103 mmol) and methyl iodide (14.6 g, 103 mmol) in acetone
(500 ml). On cooling the reaction mixture was ®ltered and
the solvent evaporated. The residue was taken into chloro-
form, ®ltered and the ®ltrate concentrated to ca. 20 ml.
Pentane (200 ml) was added and the resulting solid isolated
by suction ®ltration to give the title compound as a yellow
powder (7.24 g, 82%) mp 199±2018C; dH (500 MHz;
CDCl3) 8.71 (1H, s, H4), 8.06 (1H, d, Jˆ8.2 Hz, H5), 8.01
3.1.7. Preparation of bis[3-(1-(3,6-di-tert-butyl-2-hydroxy-
1-naphthyl)isoquinolyl)methyl] sulphide 5. Compound 26
(25 mg, 0.47 mmol) was stirred overnight with sodium
sulphide nonahydrate (6.0 mg, 2.5 mmol) in DMF (2 ml).
1
The DMF was removed in vacuo and H NMR analysis of
the residue showed 85% conversion to the diastereomeric
mix of products. Puri®cation and separation of the dia-
stereomers was achieved by preparative tlc (dichloro-
methane, Rfˆ0.40(a) and 0.36(b));
0
0
(1H, d, Jˆ9.1 Hz, H4 ), 7.86 (1H, d, Jˆ8.2 Hz, H5 ), 7.77
(1H, ddd, Jˆ8.2, 6.5, 1.6 Hz, H6), 7.54±7.49 (2H, m, H7,
0
H8), 7.44 (1H, d, Jˆ9.1 Hz, H3 ), 7.34 (1H, ddd, Jˆ8.2, 7.0,
0
0
3.1.8. Diastereomer (a). dH (500 MHz; CDCl3) 7.85 (1H,
s, H4), 7.77 (1H, d, Jˆ8.4 Hz, H5), 7.75 (1H, d, Jˆ2.1 Hz,
1.1 Hz, H6 ), 7.26 (1H, ddd, Jˆ8.5, 7.2, 1.1 Hz, H7 ), 7.03
0
(1H, d, Jˆ8.5 Hz, H8 ), 4.05 (3H, s, CO2CH3), 3.78 (3H, s,
0
0
H5 ), 7.73 (1H, s, H4 ), 7.61 (1H, dd, Jˆ8.4, 8.4 Hz, H6), 7.53
OCH3); dC (125.8 MHz; CDCl3) 166.8, 158.8, 155.0, 141.6,
135.9, 130.8, 130.7, 130.3, 129.4, 129.2, 128.3, 127.9,
127.6, 126.8, 124.7, 123.8, 123.7, 121.5, 113.5, 56.6, 52.8;
m/z (APCI1; NH3) 344 (M11, 100%); HRMS, 344.1291;
Calcd 344.1287.
(1H, d, Jˆ8.4 Hz, H8), 7.29 (1H, dd, Jˆ8.4, 8.4 Hz, H7),
0
7.21 (1H, dd, Jˆ8.9, 2.1 Hz, H7 )., 6.99 (1H, d, Jˆ8.9 Hz,
0
H8 ), 4.18 (1H, d, Jˆ14.1 Hz, CH2S), 4.11 (1H, d, Jˆ
14.1 Hz, CH2S), 1.57 (9H, s, t-butyl), 1.38 (9H, s, t-butyl);
dC (125.8 MHz; CDCl3) 158.4, 153.2, 150.2, 145.6, 139.1,
137.7, 130.7, 129.5, 128.6, 128.1, 127,4, 127.0, 126.8,
127.4, 127.0, 126.8, 124.4, 123.1, 119.1, 116.5, 37.6, 35.5,
34.5, 31.2, 29.9; m/z (APCI1; NH3) 826 (M11, 60%), 398
(100%), HRMS, 825.4454; Calcd 825.4454.
3.1.12. Preparation of 3-hydroxymethyl-1-(2-methoxy-1-
naphthyl)isoquinoline 22. 21 (8.60 g, 25.0 mmol) was
dissolved in dry THF (250 ml) and lithium borohydride
(1.09 g, 50.0 mmol) was added in solid portions over
10 min. The reaction mixture was stirred for 4 h, then
quenched by the sequential addition of water (50 ml) and
1 M hydrochloric acid (25 ml). The THF was removed on
the rotary evaporator, then the product extracted into chloro-
form (2£75 ml), dried (MgSO4) and the solvents evaporated
to give the title compound as a pale yellow solid (7.88 g,
95%) mp 213±2148C; dH (500 MHz; CDCl3) 8.06 (1H, d,
3.1.9. Diastereomer (b). dH (500 MHz; CDCl3) 7.88 (1H,
0
s, H4), 7.76 (1H, d, Jˆ2.1 Hz, H5 ), 7.72 (1H, d, Jˆ8.4 Hz,
0
H5), 7.72 (1H, s, H4 ), 7.26 (1H, dd, Jˆ8.4, 7.3 Hz, H6), 7.45
(1H, d, Jˆ8.5 Hz, H8), 7.20 (1H, dd, Jˆ8.5, 7.5 Hz, H7),
0
7.19 (1H, dd, Jˆ8.9, 2.1 Hz, H7 ), 6.96 1H, d, Jˆ8.9 Hz,
0
H8 ), 4.14 (1H, d, Jˆ14.3 Hz, CH2S), 4.11 (1H, d, Jˆ
0
14.3 Hz, CH2S), 1.64 (9H, s, t-butyl), 1.37 (9H, s, t-butyl);
m/z (APCI1; NH3) 826 (M11, 70%), 398 (100%).
Jˆ9.1 Hz, H4 ), 7.95 (1H, d, Jˆ8.3 Hz, H5), 7.88 (1H, d,
0
Jˆ8.2 Hz, H5 ), 7.82 (1H, s, H4), 7.75 (1H, dd, Jˆ8.3,
8.3 Hz, H6), 7.55 (1H, d, Jˆ8.4 Hz, H8), 7.46 (1H, d, Jˆ
0
3.1.10. Preparation of 3-carboxy-1-(2-methoxy-1-
naphthyl)isoquinoline 20. A solution of tetrakis(triphenyl-
phosphine)palladium(0) (1.80 g, 1.56 mmol) in DME
(150 ml) was added to a 1 l, three-necked round bottomed
¯ask, containing 19 (13.8 g, 62.2 mmol), and stirred under
argon for 20 min. Solutions of 7 (12.6 g, 62.2 mmol) in
ethanol (100 ml), and potassium carbonate (25.8 g,
18.6 mmol) in water (100 ml) were added and the mixture
heated at 1008C overnight. On cooling, the reaction mixture
was ®ltered and the solvents evaporated. Water (150 ml)
was added to the residue and the solution was washed
with dichloromethane (3£100 ml). The aqueous layer was
then acidi®ed with 1 M hydrochloric acid and the resultant
9.1 Hz, H3 ), 7.44 (1H, dd, Jˆ8.4, 8.3 Hz, H7), 7.35 (1H, dd,
0
0
Jˆ8.2, 8.2 Hz, H6 ), 7.27 (1H, dd, Jˆ8.5, 8.3 Hz, H7 ), 6.99
0
(1H, d, Jˆ8.5 Hz, H8 ), 5.03 (2H, s, OCH2), 3.82 (3H, s,
OCH3); dC (125.8 MHz; CDCl3) 157.4, 155.1, 151.1,
137.3, 133.5, 131.6, 131.4, 128.9, 128.1, 128.0, 127.9,
127.6, 127.2, 127.1, 124.4, 123.9, 117.5, 113.4, 64.2, 56.7;
m/z (APCI1; NH3) 315 (M11, 100%); HRMS, 316.1329;
Calcd 316.1338.
3.1.13. Preparation of 3-bromomethyl-1-(2-hydroxy-1-
naphthyl)isoquinoline 23. To a solution of 3-hydroxy-
methyl-1-(2-methoxy-1-naphthyl)isoquinoline (6.67 g, 21.2
mmol) in dry dichloromethane (150 ml) was added boron

S. C. Tucker et al. / Tetrahedron 57 (2001) 2545±2554
2553
tribromide (4.00 ml, 42.4 mmol) dropwise with stirring. The
resulting black solution was stirred overnight, then the reac-
tion mixture quenched by the careful addition of water
(50 ml) and 0.5 M sodium hydroxide solution (25 ml). The
dichloromethane layer was separated and the aqueous layer
extracted with ethyl acetate (2£75 ml). The combined
organics were dried (MgSO4), ®ltered and the solvents
evaporated, to give a residue which on trituration with
pentane gave the title compound as a bright yellow powder
(5.95 g, 77%) mp decomp .2408C; dH (500 MHz; CDCl3)
chloroform (5 ml) for 10 min. 1H NMR analysis of the solu-
tion indicated three species were present: uncomplexed
starting material (49%), palladium complex (major dia-
stereomer) (38%), and palladium complex (minor dia-
stereomer) (13%). The solvent was evaporated, and the
residue puri®ed by ¯ash column chromatography on silica
(dichloromethane) to give uncomplexed 13 (75 mg, 38%)
which was dissolved in chloroform (50 mg in 5 ml) and kept
at 238C. Its optical rotation was measured over a period of
time. Further elution of the column (CH2Cl2) gave the major
diastereomer of the palladium complex; mp 190±1928C; dH
(500 MHz; CDCl3) 9.09 (1H, d, Jˆ6.4 Hz), 8.00 (1H, d, Jˆ
0
7.94 (1H, d, Jˆ8.2 Hz, H5), 7.93 (1H, d, Jˆ8.9 Hz, H4 ),
0
7.88 (1H, s, H4), 7.87 (1H, d, Jˆ8.3 Hz, H5 ), 7.74 (1H, ddd,
0
Jˆ8.2, 7.0, 0.9 Hz, H6), 7.63 (1H, d, Jˆ8.5 Hz, H8), 7.43
(1H, ddd, Jˆ8.5, 7.1, 1.0 Hz, H7), 7.39 (1H, d, Jˆ8.9 Hz,
6.4 Hz), 7.99 (1H, d, Jˆ8.2 Hz), 7.89 (1H, s, H4 ), 7.77 (1H,
ddd, Jˆ8.2, 7.9, 1.6 Hz), 7.66 (1H, d, Jˆ7.2 Hz), 7.44±7.40
(3H, m), 7.24±7.19 (4H, m), 6.58 (1H, d, Jˆ8.5 Hz), 6.25
(1H, dd, Jˆ8.8, 1.7 Hz), 6.16 (1H, d, Jˆ8.8 Hz), 3.73 (1H,
q, Jˆ6.4 Hz), 2.70 (3H, s), 2.48 (3H, s), 1.65 (9H, s), 0.80
(9H, s), 0.45 (3H, d, Jˆ6.4 Hz); dC (125 MHz; CDCl3)
162.8, 151.4, 146.4, 146.1, 145.5, 144.0, 142.9, 135.8,
132.2, 131.5, 131.0, 129.1, 128.9, 128.5, 128.1, 127.8,
127.0, 126.7, 125.2, 125.1, 124.3, 123.8, 123.4, 123.2,
122.6, 121.6, 73.9, 53.3, 49.1, 35.6, 33.9, 30.4, 30.4, 20.9;
m/z (Electrospray)ˆ687.6 (M11).
0
0
H3 ), 7.35 (1H, ddd, Jˆ8.3, 7.1, 1.1 Hz, H6 ), 7.26 (1H, ddd,
0
0
Jˆ8.4, 7.1, 1.3 Hz, H7 ), 7.20 (1H, d, Jˆ8.4 Hz, H8 ), 4.89
(1H, d, Jˆ10.3 Hz, CH2Br), 4.75 (1H, d, Jˆ10.3 Hz,
CH2Br); dC (125.8 MHz; CDCl3) 157.9, 153.6, 149.0,
137.7, 132.8, 131.4, 131.2, 128.9, 128.4, 128.3, 127.9,
127.3, 126.5, 125.1, 123.4, 119.8, 119.1, 116.5; m/z
(APCI1; NH3) 365 (M11, 100%).
3.1.14. Preparation of bis[3-(1-(2-hydroxy-1-naphthyl)-
isoquinolyl)methyl]sulphide 4. 23 (1.00 g, 2.75 mmol)
was heated at 1008C with sodium sulphide nonahydrate
(330 mg, 1.37 mmol) in DMF (10 ml) for 10 min. The
DMF was removed in vacuo and the residue puri®ed by
column chromatography (1:1 ethyl acetate/pentane, Rfˆ
0.35) to yield the title compound as a bright orange crystal-
line solid (511 mg, 62%) mp 94±1258C; nmax (KBr disc)/
cm21 3500±3350s (O±H), 3057w (Ar C±H), 2360s (sp3 C±
H), 2341s (sp3 C±H), 1622s (Ar CvN), 1587m (Ar CvC),
1558m (Ar CvC), 1512m (Ar CvC), 1347s, 1262s, 1245s,
816m, 749s; dH (500 MHz; CDCl3) 7.85 (1H, d, Jˆ8.1 Hz,
3.1.17. Racemisation studies on 26. 26 (200 mg,
0.420 mmol) and 14 (71.0 mg, 1.05 mmol) were stirred
overnight in chloroform (5 ml). H NMR analysis of the
1
solution indicated two species were present: uncomplexed
starting material (50%), and a single palladium complex
(50%). The solvent was evaporated, and the residue puri®ed
by ¯ash column chromatography on silica (dichloro-
methane) to give uncomplexed starting material (81 mg,
41%) which was dissolved in chloroform (50 mg in 5 ml)
and kept at 238C. Its optical rotation was measured over a
period of time. Further elution of the column gave the
palladium complex; mp 165±1678C; dH (500 MHz;
CDCl3) 8.48 (1H, s), 8.02 (1H, d, Jˆ8.3 Hz), 7.90 (1H, s),
7.77 (1H, ddd, Jˆ8.3, 6.5, 1.5 Hz), 7.64 (1H, d, Jˆ7.4 Hz),
7.42±7.35 (4H, m), 7.27±7.19 (3H, m), 7.17 (1H, d, Jˆ
8.6 Hz), 6.33 (1H, d, Jˆ8.6 Hz), 6.28 (1H, dd, Jˆ8.9,
1.9 Hz), 6.25 (1H, d, Jˆ13.1 Hz), 6.18 (1H, d, Jˆ8.9 Hz),
5.70 (1H, d, Jˆ13.1 Hz), 3.76 (1H, q, Jˆ6.4 Hz), 2.78 (3H,
s), 2.50 (3H, s), 1.64 (9H, s), 0.80 (9H, s), 0.43 (3H, d,
Jˆ6.4 Hz); dC (500 MHz; CDCl3) 162.6, 151.4, 148.0,
146.3, 146.2, 142.9, 136.7, 132.5, 131.8, 131.5, 129.1,
129.0, 128.5, 128.3, 128.2, 128.1, 127.8, 127.3, 126.8,
125.3, 124.5, 124.2, 124.0, 123.6, 123.3, 122.6, 121.5,
73.9, 53.5, 49.1, 35.6, 33.9, 33.5, 30.5, 20.9; m/z (Electro-
spray)ˆ781.4 (M11).
0
0
H4 ), 7.84 (1H, d, Jˆ8.3 Hz, H4 ), 7.81 (2H, s, H4), 7.78 (1H,
d, Jˆ8.3 Hz, H5), 7.71 (1H, d, Jˆ8.2 Hz, H5), 7.60±7.41
0
0
0
(6H, m, H6, H8, H5 ), 7.36±7.14 (8H, m, H7, H6 , H7 , H3 ),
0
0
0
7.07 (1H, d, Jˆ8.8 Hz, H8 ), 6.89 (1H, d, Jˆ8.8 Hz, H8 ),
4.20 (1H, d, Jˆ14.1 Hz, CH2S), 4.04 (1H, d, Jˆ14.1 Hz,
CH2S), 4.01 (1H, d, Jˆ14.2 Hz, CH2S), 3.98 (1H, d, Jˆ
14.2 Hz, CH2S); dC (125.8 MHz; CDCl3) 157.6, 157.0,
153.7, 153.4, 150.7, 137.7, 137.4, 132.8, 131.1, 131.0,
130.8, 130.7, 129.0, 128.7, 128.2, 128.1, 127.0, 126.9,
126.8, 126.3, 125.3, 125.0, 124.6, 123.6, 123.3, 123.2,
120.1, 119.9, 119.1, 118.9, 118.3, 116.6, 38.5, 36.5; m/z
(APCI1; NH3) 601 (M11, 100%); HRMS, 601.1958;
Calcd 601.1950.
3.1.15. Racemisation studies on compound 3. Compound
3 (200 mg, 0.740 mmol) and 14 (125 mg, 0.180 mmol) were
stirred in chloroform (20 ml) for 2 h. H NMR analysis of
1
3.1.18. Racemisation studies on 23. 23 (1.72 g, 4.73 mmol)
and 14 (805 mg, 1.18 mmol) were stirred overnight in
chloroform (50 ml). 1H NMR analysis of the solution
indicated three species were present: uncomplexed starting
material (48%), palladium complex (major diastereomer)
(50%) and another palladium complex (minor diastereomer)
(2%). The solvent was evaporated and the residue puri®ed
by ¯ash chromatography on silica gel (3:1 pentane/ethyl
acetate) to give uncomplexed 3-bromomethyl-1-(2-hy-
droxy-1-naphthyl)isoquinoline (652 mg, 38%) which was
dissolved in chloroform (250 mg in 50 ml) and kept at
238C. Optical rotation measurements were made periodic-
ally. Further elution of the column (ethyl acetate) gave the
the solution indicated three species were present: uncom-
plexed starting material (60%), palladium complex (major
diastereomer) (35%), and palladium complex (minor dia-
stereomer) (5%). The solution was concentrated to ca.
5 ml, and on standing a white precipitate formed. This
was ®ltered off to give a pure sample of uncomplexed 3
(46 mg, 30%) which was dissolved in chloroform (25 mg
in 5 ml) and kept at 238C. Its optical rotation was measured
periodically.
3.1.16. Racemisation studies on 13. 13 (200 mg,
0.520 mmol) and 14 (89 mg, 0.13 mmol) were stirred in

2554
S. C. Tucker et al. / Tetrahedron 57 (2001) 2545±2554
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Soc.-Dalton Trans. 1999, 2411±2413. Li, Z.; Fernandez,
M.; Jacobsen, E. N. Org. Lett. 1999, 1, 1611±1613.
Nishikori, H.; Katsuki, T. Tetrahedron Lett. 1996, 37,
9245±9248.
major palladium diastereomer; dH (500 MHz; CDCl3) 8.52
(1H, s), 8.05 (1H, d, Jˆ8.3 Hz), 7.97 (1H, d, Jˆ8.7 Hz),
7.81 (1H, dd, Jˆ8.3, 7.5 Hz), 7.74 (1H, s), 7.66 (1H, d,
Jˆ7.7 Hz), 7.59 (1H, d, Jˆ8.1 Hz), 7.56 (1H, d, Jˆ
8.7 Hz), 7.41 (1H, dd, Jˆ8.2, 7.5 Hz), 7.30±7.24 (5H, m),
7.17 (1H, d, Jˆ8.5 Hz), 6.84 (1H, ddd, Jˆ8.0, 5.3, 2.7 Hz),
6.45 (1H, d, Jˆ8.0 Hz), 6.36 (1H, d, Jˆ8.5 Hz), 6.18 (1H, d,
Jˆ13.0 Hz), 5.71 (1H, d, Jˆ13.0 Hz), 3.82 (1H, q, Jˆ
6.4 Hz), 2.84 (3H, s), 2.56 (3H, s), 0.49 (3H, d, Jˆ
6.4 Hz); dC (125.8 MHz; CDCl3) 161.4 (C10), 152.3
(ArC), 148.4 (ArC), 146.9 (ArC), 144.2 (ArC), 136.8
(ArC), 132.7 (ArC), 131.7 (ArC), 131.5 (ArCH), 131.5
(ArCH), 131.4 (ArCH), 131.4 (ArC), 129.3 (ArC), 129.2
(ArCH), 128.5 (ArCH), 128.2 (ArC), 128.1 (ArCH), 127.9
(ArC), 127.0 (ArCH), 126.9 (ArCH), 125.5 (ArCH), 125.4
(ArCH), 124.7 (ArCH), 124.2 (ArCH), 123.8 (ArCH), 123.7
(ArCH), 122.9 (ArCH), 122.8 (ArCH), 74.0 (CHCH3), 53.4
(NCH3), 49.1 (NCH3), 33.3 (CH2Br), 21.1 (CHCH3); m/z
(FAB) 669 (M1).
8. Larrow, J. F.; Jacobsen, E. N. J. Am. Chem. Soc. 1994, 116,
12129±12130. Hamada, T.; Irie, R.; Mihara, J.; Hamachi, K.;
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Katsuki, T. Tetrahedron 1999, 55, 9439±9454. Punniyamurthy,
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8295±8298.
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Chem. Soc. 1996, 118, 7420±7421. Lebel, H.; Jacobsen, E. N.
Tetrahedron Lett. 1999, 40, 7303±7306. Martinez, L. E.;
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Chem. Soc. 1995, 117, 5897±5898. Ready, J. M.; Jacobsen,
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Acknowledgements
We thank Unilever Research (Port Sunlight) for a CASE
award to S. C. T., and EPSRC for support. Mrs E. McGuin-
ness was very helpful in the acquisition of NMR spectra,
and Dr R. T. Aplin in the acquisition of MS. Mrs V.
Lambourn is thanked for combustion analyses. We thank
Dr D. J. Bayston for a ®rst synthesis of compound 19.
10. Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron:
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11. Braddock, D. C.; Tucker, S. C.; Brown, J. M. Bull. Soc. Chim.
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