Sulfoxides as 'traceless' resolving agents for the synthesis of atropisomers by dynamic or classical resolution

Article abstract of DOI:10.1016/j.tet.2004.01.099

Reacting (-)-menthyl sulfinate with an atropisomeric but racemic aryllithium gives two atropdiastereoisomeric sulfoxides. Separation (by chromatography or crystallisation) and sulfoxide-lithium exchange of each diastereoisomer regenerates the aryllithium in enantiomerically pure form which can be quenched with a range of electrophiles with retention of stereochemical integrity. Overall the reaction sequence is a resolution but without the need for an acidic or basic substituent - a 'traceless' method. In certain instances, for example when the nucleophile is an ortholithiated peri-substituted 1-naphthamide, the diastereoisomeric sulfoxides may be interconverted thermally. This allows a dynamic resolution, under thermodynamic control, and hence in principle can give yields of the final products of greater than 50%. The utility of the method is demonstrated by the synthesis of a known atropisomeric phosphine ligand.

Full text of DOI:10.1016/j.tet.2004.01.099

Tetrahedron 60 (2004) 4387–4397
Sulfoxides as ‘traceless’ resolving agents for the synthesis
of atropisomers by dynamic or classical resolution
a
a
a
Jonathan Clayden,a Przemyslaw M. Kubinski, Federica Sammiceli, Madeleine Helliwell
,
*
and Louis Dioraziob
aDepartment of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
bAstraZeneca PRD, Charter Way, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, UK
Received 19 November 2003; revised 19 January 2004; accepted 21 January 2004
Abstract—Reacting (2)-menthyl sulfinate with an atropisomeric but racemic aryllithium gives two atropdiastereoisomeric sulfoxides.
Separation (by chromatography or crystallisation) and sulfoxide–lithium exchange of each diastereoisomer regenerates the aryllithium in
enantiomerically pure form which can be quenched with a range of electrophiles with retention of stereochemical integrity. Overall the
reaction sequence is a resolution but without the need for an acidic or basic substituent—a ‘traceless’ method. In certain instances, for
example when the nucleophile is an ortholithiated peri-substituted 1-naphthamide, the diastereoisomeric sulfoxides may be interconverted
thermally. This allows a dynamic resolution, under thermodynamic control, and hence in principle can give yields of the final products of
greater than 50%. The utility of the method is demonstrated by the synthesis of a known atropisomeric phosphine ligand.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
complex with di-O-benzoyl tartrate than the other.6 The
general asymmetric synthesis of chiral binaphthyls from a
single precursor is made harder by the unfortunate fact that
although the diamine 3 can be resolved, racemisation of the
intermediates in its diazotisation–substitution reactions is
rapid.8
Many of the most effective ligands for asymmetric catalysis
by metals are atropisomeric.1–3 Although there are an
increasing number of asymmetric methods for the construc-
tion of atropisomeric biaryls by asymmetric coupling
methods,4,5 almost all practical syntheses of ligands rely
on resolution.6,7 The acidic or basic groups required for
resolution are rarely present in the final target ligand, and
this can place constraints on the choice of synthetic route
and therefore the ability to vary a single route to provide a
range of ligands. In the case of BINAP 1, a resolution of the
bis-phosphine oxide 2 is carried out—one enantiomer of this
compound fortunately forms a much more crystalline 1:1
We recently reported the use of sulfoxides as ‘chiral
equivalents’ of anions in the asymmetric synthesis of some
atropisomeric amides.9 The sulfoxides have several features
which make them amenable to use in this way: firstly, they
may be constructed in enantiomerically pure form by any of
a number of methods, the most important for our purposes
being the Andersen substitution of (2)-menthyl sulfinate
4.10,11 Secondly, they have electronic properties which
exaggerate the contrast between the physical properties of
the two stereoisomeric atropisomers, mainly because of
dipole orientation.9 Thirdly, they may undergo sulfoxide–
lithium exchange—nucleophilic substitution at sulfur—to
regenerate a nucleophilic organometallic (organolithium)
for use in further substitution reactions.12–19
In this paper we show that these properties are also
applicable to the synthesis of some binaphthyl atropisomers,
along with a known atropisomeric amidophosphine ligand.
In one sequence, we aim to exploit the influence of the
dipole of the intermediate binaphthylsulfoxide on the
relative polarity of the atropisomeric diastereoisomers,
allowing their chromatographic separation. In the other,
the dipole governs the relative stability of a pair of
diastereoisomeric atropisomers, and allows the quantitative
Keywords: Sulfoxides; Atropisomers; Resolution; Binaphthyls.
*
Corresponding author. Tel.: þ44-161-275-4612; fax: þ44-161-275-4939;
e-mail address: j.p.clayden@man.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.099

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J. Clayden et al. / Tetrahedron 60 (2004) 4387–4397
conversion of one diastereoisomer to the other. The
resolution may therefore be dynamic in nature, and can
yield significantly more than 50% of an enantiomerically
pure product.
We found the reported synthesis of 2,20-dibromobinaphthyl
6 from 2,20dihydroxybinaphthyl (binaphthol) 5 to be a
useful source of starting bromobinaphthalenes 7 and 9:6 in
our hands 8 was always formed as a by-product during the
vigorous conversion of 5 to 6. The phenol 8 was methylated,
giving 9 (Scheme 1).
2. Results and discussion
Further supplies of the phenol 8 were obtained from the
dibromobinaphthyl 6. Clean monolithiation with 2 equiv.
t-BuLi gave an organolithium, which was quenched with
trimethyl borate and then oxidised to yield 8. The same
organolithium was hydrolysed to yield the bromide 7.
2.1. Synthesis of atropisomeric binaphthyls by resolution
via sulfoxides
Our plan was to use sulfoxide–lithium exchange20 from an
enantiomerically pure binaphthylsulfoxide 12 to generate a
chiral, atropisomeric binaphthyllithium 10 which we hoped
to quench with retention of stereochemistry, yielding
enantiomerically enriched binaphthyls 11. While the
configurational stability about the chiral axis of biaryl-
lithiums has not been studied in detail, it appears to depend
on the nature of the substituent at0the 2-position of the other
ring. For example, 2-lithio-2 -phosphanyl-substituted
binaphthyls are configurationally unstable while their
borane adducts are configurationally stable.21–23 2,20-
Dilithio-1,10-binaphthyl is known to be configurationally
stable to 244 8C.24
The bromobinaphthyls 6, 7 and 9 were used as starting
materials for the synthesis of some sulfoxides 12. t-BuLi
gave the racemic organolithiums 10, and reaction with
(1R,2S,5R,SS)-(2)-menthyl p-toluenesulfinate 425 gener-
ated diastereoisomeric pairs of sulfoxides M- and P-12a–
c. Reaction of 10 with achiral electrophiles MeI, NH4Cl and
p-Tol2S2 gave racemic standards 11a, 11b and 11c for
comparison with the enantiomerically pure samples pro-
duced later (see below).
The diastereoisomers 12b were obtained, as expected, in a
1:1 ratio, and were readily separated by fractional crystal-
lisation, which gave a 35% yield of P-12b and, by
crystallisation from the mother liquors, a 31% yield of
M-12b, both of which were identified by X-ray crystal-
lography (Figs. 1 and 2).26 Nucleophilic substitution with
(2)-menthyl p-toluenesulfinate occasionally proceeds with
incomplete stereospecificity:15 later results, however, con-
firmed that both M-12b and P-12b obtained in this way were
enantiomerically pure.
The diastereoisomers of sulfoxides 12a and 12c unfortu-
nately turned out to be inseparable apart from by HPLC,
which permitted the isolation of small amounts of each
diastereoisomer of the two compounds, though in these
cases we were unable to unequivocally assign stereochem-
istry to the products. The diastereoisomers of 12a obtained
in this way were compared with the racemic sulfoxides
obtained when the racemic sulfide 11c was oxidised with
m-CPBA, and were .99% enantiomerically pure by HPLC.
Scheme 1. Synthesis of starting bromobinaphthalenes.
Figure 1. X-ray crystal structure of P-12b.

J. Clayden et al. / Tetrahedron 60 (2004) 4387–4397
4389
The oxidation of 11c gave the diastereoisomers of 12a in a
54:46 ratio.
Treatment of 6 with 4 equiv. of t-BuLi and 2 equiv. of
sulfinate 4 yielded a much more readily separable pair of
diastereoisomeric bis-sulfoxides 14, whose identity was
confirmed by X-ray crystal structure of the more crystalline
of the pair (Fig. 3).
The separated diastereoisomers of the sulfoxides 12b were
subjected to sulfoxide–lithium exchange9,18,20 by treatment
with 2.1 equiv. t-BuLi to yield the enantiomerically pure
binaphthyllithiums M- and P-10b. These organolithiums
were evidently configurationally stable about the Ar–Ar
axis over the period of the reaction, because methylation of
each enantiomer yielded the enantiomerically pure
binaphthyls M- and P-11a in good yield and with .99%
ee in each case. Protonation yielded the enantiomerically
enriched binaphthyls 11b with some loss of enantiomeric
excess (Scheme 2), which we attribute to partial racemisa-
tion of the product during isolation.
Figure 2. X-ray crystal structure of M-12b.
Figure 3. X-ray crystal structure of P-14.

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The asymmetric synthesis of 11a and 11b, although it is
accomplished by resolution, is significant because of the
lack of functionality in the final products of the sequence—
the sulfoxide is ‘traceless” as a resolving agent. In the model
cases chosen here, extension of the method to further
compounds was hampered by the unexpected inability to
separate the sulfoxide diastereoisomers in some cases.
However, the strategy clearly has potential for application to
more valuable biaryl targets. We had furthermore hoped that
heating mixtures of the diastereoisomers of 12a or 12b
would allow enrichment of the mixture in the more stable of
each diastereoisomeric pair, and thus allow us to convert
the binaphthyl resolutions into dynamic resolutions under
thermodynamic control.9,27,28 However, in no case (heating
either diastereoisomer separately or a mixture at tempera-
tures up to 135 8C in xylene) did we see a change in the
diastereoisomeric ratio. In Section 2.2, we describe the
synthesis of a known ligand by a related sulfoxide-based
method, which avoids the loss of 50% yield inherent in a
classical resolution by incorporating just such an equili-
bration step into the resolution.
2.2. Synthesis of an atropisomeric amidophosphine by
dynamic resolution
In 2002, Dai reported that the amidophosphine 18 (R¼PPh2)
catalysed the asymmetric allylic alkylation of dimethyl-
malonate.29 Secondary amidophosphines had previously
been used as chiral ligands by Trost,30 and we had shown
that the chiral axis in tertiary amidophosphine ligands is the
stereochemistry-controlling feature in some similar allylic
alkylations.31,32 Dai made phosphine 18, whose configura-
tional stability is ensured by the electronegative peri
substituent,33 by resolving the precursor phenol as a pair
of diastereoisomeric camphanate esters.
For our asymmetric synthesis of 18, which was under way
before Dai’s publication, we employed the sulfoxide-based
strategy outlined above. We hoped that the known ability of
the sulfoxide dipole to bias the conformation of an adjacent
aromatic amide such that the CvO and S–O dipoles oppose
Scheme 2. Resolution via binaphthylsulfoxides.
Figure 4. X-ray crystal structure of P-17.

J. Clayden et al. / Tetrahedron 60 (2004) 4387–4397
4391
one another,9 along with the relatively poor ability of second
row elements (Si, P, S) to provide a steric barrier to amide
bond rotation,32,34 would allow us to make this ligand
without recourse to a classical resolution, with the
associated maximum 50% yield.
However, in the case of 17, we found that heating to 100 8C
for 12 h quantitatively converted M-17 to P-17, while the
same treatment of P-17 left it unchanged. Clearly, under
conditions where M- and P-17 may interconvert, the
equilibrium favours P-17 to a very great extent. Application
of the thermal equilibration step in the synthesis of the
sulfoxides gave us a way of making, in a single trans-
formation, the enantiomerically and diastereoisomerically
pure sulfoxide P-17 from the racemic amide 15 with an
overall yield of .80%.
The 8-methoxynaphthamide 15 was made on a multigram
scale by a published route35 from 1,8-naphthalic anhydride.
Ortholithiation with sec-BuLi in THF and reaction with
(2)-menthyl sulfinate 4 gave the sulfoxides 17 in as a
mixture of diastereoisomers. The diastereoisomers could be
separated by flash chromatography, allowing the isolation of
the diastereoisomers in 41 and 40% yield, respectively, and
an X-ray crystal structure (Fig. 4) of one of them P-17)
confirmed their relative and absolute stereochemistry.
On treatment with t-BuLi (1.5 equiv.) in THF, the sulfoxide
P-17 underwent sulfoxide–lithium exchange to yield the
enantiomerically pure organolithium M-16, which was
quenched with the selection of electrophiles as shown in
Scheme 3. Racemic standards of 18 and 19 were made by
direct lithiation-electrophilic quench from 15.
In the light of previous studies of the preferred conformation
of 2-sulfinyl amides,9 we expected M-17 to be the less stable
of the two diastereoisomers. 8-Substituted naphthamides
typically have very high barriers to Ar–CO rotation,
especially when a non-hydrogen 2-substituent is present.33
With chlorodiphenylphosphine, the ligand 18 (R¼PPh2)
was formed in 60% yield (provided a non-aqueous work-up
was employed32) and with .95% ee. Most of the remaining
Scheme 3. Asymmetric synthesis of atropisomeric amides by dynamic resolution employing amidosulfoxides.

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J. Clayden et al. / Tetrahedron 60 (2004) 4387–4397
material (30% isolated yield) was enantiomerically enriched
(.95% ee) 15, which was also easily synthesised in
quantitative yield simply by protonation of M-16, a reaction
which amounts to a direct dynamic thermodynamic
resolution28 of 15. Use (or recycling) of this protonated
material gives the phosphine in an improved 70% yield, but
over two steps, and allows the overall yield of phosphine
after a couple of recycling steps to approach 85–90%.
was heated with an oil bath to facilitate stirring. The
reaction mixture, cooled below 70 8C, was dissolved in
100 mL of hot toluene, and filtered through a sintered-glass
funnel. The solid material was extracted with a boiling
mixture of toluene and petrol, and the combined extracts
were evaporated. The resulting brown oil was repeatedly
purified by flash chromatography with a mixture petrol/
EtOAc (4:1) as eluent to give the title compound 6 (3.81 g,
9.24 mmol, 11%) as white plates. dH (300 MHz, CDCl3):
7.98 (2H, d, J¼8.2 Hz), 7.92 (2H, d, J¼8.8 Hz), 7.86 (2H, d,
J¼8.8 Hz), 7.54 (2H, dd, J¼6.9, 8.1 Hz), 7.35 (2H, dd,
J¼6.9, 8.5 Hz), 7.13 (2H, d, J¼8.5 Hz); dC (75 MHz,
CDCl3): 137.1, 133.3, 132.2, 129.9, 129.7, 128.2, 127.3,
126.3, 125.8, 122.7.
Methylation of M-16 gave the amide 19 in 74% yield and
.99% ee, which was laterally lithiated and quenched with
cyclobutanone to return 20 in 58% yield and .95% ee.36
3. Conclusion
Also obtained was 20-bromo-[1,10]binaphthalenyl-2-ol 8
(4.98 g, 14.28 mmol, 17%).
A sulfinyl substituent can bias the relative stability of a pair
of diastereoisomeric peri-substituted atropisomeric amides
such that one becomes much more stable than the other,
allowing an efficient and high yield dynamic resolution to be
achieved under thermodynamic control. The products of
the resolution include an unusual amidophosphine ligand
previously shown to be useful in allylic alkylation.
4.1.2. 2-Bromo-[1,10]binaphthalenyl 7.38 t-BuLi (0.57 mL,
1.7 M solution in pentane, 2.00 equiv., 0.976 mmol) was
added dropwise at 278 8C to a solution of 2,20-dibromo-
[1,10]binaphthalenyl 6 (0.200 g, 0.488 mmol) in dry THF
(5 mL) and stirred for 15 min under nitrogen. The reaction
was then quenched with a saturated solution of NH4Cl
(10 mL) and allowed to warm to room temperature. The two
layers were separated; the organic phase was washed with
sat. NH4Cl, dried over MgSO4 and evaporated, to give a
crude product which was purified by flash chromatography
with eluent petrol/EtOAc (20:1); the title compound was
obtained as yellow solid (0.1296 g, 0.390 mmol, 80%),
Rf 0.53 (10% EtOAc in petrol). dH (300 MHz, CDCl3):
8.07–8.01 (2H, m), 7.96 (1H, dd, J¼8.4, 0.6 Hz), 7.90–
7.80 (2H, m), 7.69 (1H, dd, J¼8.1, 7.2 Hz) 7.57–7.50 (3H,
m), 7.47 (1H, dd, J¼7.2, 1.2 Hz), 7.40–7.23 (3H, m).
In the binaphthyl series, the barriers to rotation are too high
for similar dynamic resolutions to be achieved, but in
limited cases the sulfoxide can be used as a means of
resolving the binaphthyls classically, and then replaced with
any of a range of substituents, including H or Me. The
products of such ‘traceless’ resolutions are rather more
difficult to obtain by standard resolution methods. Whether
sulfoxides will have a use in the asymmetric synthesis of
less hindered biaryls under dynamic resolution conditions
remains to be seen.37
4.1.3. 20-Bromo-[1,10]binaphthalenyl-2-ol 8. t-BuLi
(0.84 mL, 1.7 M solution in pentane, 1.95 equiv.,
1.427 mmol) was added dropwise at 278 8C to a solution
of 2,20-dibromo-[1,10]binaphthalenyl 6 (0.300 g, 0.732
mmol) in dry THF (10 mL) and stirred for 15 min under
nitrogen. Dry trimethyl borate (0.10 mL, 1.20 equiv.,
0.878 mmol) was added dropwise at 278 8C, and the cold
bath was replaced by an ice bath. After 1 h the reaction was
quenched with 2.5 M NaOH solution in 30% hydrogen
peroxide (10 mL) and then allowed to warm to room
temperature. The reaction mixture was acidified with 2 M
HCl solution to pH ,6 and the two layers were separated;
the aqueous phase was extracted with EtOAc (2£20 mL)
and the combined organic fractions were washed with brine
(50 mL). The organic phase was dried over MgSO4 and
evaporated, to give a crude product, which was purified by
flash chromatography eluting with petrol/EtOAc (20:1). The
title compound was obtained as a yellow solid (0.1401 g,
0.403 mmol, 55%), Rf 0.38 (petrol/EtOAc 5:1), mp 166–
169 8C;. nmax (CHCl3)/cm21 3583–3274 (OH), 1619, 1581,
1503, 811, 747; dH (300 MHz, CDCl3): 8.02–7.86 (5H, m),
7.58 (1H, td, J¼8.1, 1.6 Hz), 7.43–7.30 (5H, m), 7.05 (1H,
d, J¼8.4 Hz), 4.89 (1H, br, OH); dC (75 MHz, CDCl3):
150.7, 134.2, 132.9, 132.7, 131.9, 130.5, 130.4, 130.3,
129.0, 128.3, 128.2, 127.8, 126.9, 126.8, 126.1, 124.8,
4. Experimental
4.1. General methods have been published previously32
4.1.1. 2,20-Dibromo-[1,10]binaphthalenyl 6.8 By the
method of Miyashita and co-workers,8 a 500 mL three-
neck round bottom flask was equipped with mechanical
stirrer, thermometer and dropping funnel. The flask was
charged with triphenylphosphine (48 g, 0.183 mol) and
acetonitrile (150 mL), previously distilled over calcium
hydride under nitrogen; the solid was dissolved by warming
the flask with hot water while stirring. The solution was then
cooled by means of an ice bath, and bromine (10 mL,
0.194 mol) was added dropwise over a period of 30 in.
The cold bath was removed and commercially available
(^)-2,20-hydroxy-1,10-binaphthyl 5 (24 g, 0.084 mol) was
added; the resulting slurry was heated with an oil bath at
60 8C while stirring for 30 min. Most of the solvent was
removed by distillation under reduced pressure slowly
increasing the temperature from 60 to 150 8C. The
temperature was raised carefully to 230 8C with a sand
bath, and an exothermic reaction occurred, with evolution of
HBr. The reaction mixture was stirred at this temperature for
1 h. The temperature was increased and kept at 300 8C with
a heating mantle for 30 min. The reaction mixture was
allowed to cool to ca. 200 8C while stirring. Celite (200 mL)
was added to the resulting thick black paste, and the flask
81
124.3, 123.6, 118.2, 117.7; m/z (EI) 350 (Mþ Br, 100%),
348 (Mþ Br, 79%), 269 (73%). Found Mþ 348.0148,
79
C20H13BrO requires Mþ 348.0150.

J. Clayden et al. / Tetrahedron 60 (2004) 4387–4397
4393
4.1.4.
20-Bromo-2-methoxy-[1,10]binaphthalenyl
9.
132.8, 132.5, 130.9, 129.4, 129.0, 128.6, 128.3, 127.8,
127.3, 126.9, 126.4, 126.2, 125.4, 124.6, 123.2, 119.8,
117.0, 113.2, 56.5, 21.1.
Methyl iodide (0.51 mL, 10.00 equiv., 10.540 mmol) and
potassium carbonate (0.7280 g, 5.00 equiv.0, 5.270 mmol)
were added to a stirred solution of 2 -bromo-[1,10]-
binaphthalenyl-2-ol 8 (0.3681 g, 1.054 mmol) in acetone
(7.50 mL) under nitrogen. The reaction mixture was heated
under reflux for 24 h. After cooling, the mixture was filtered
and the filtrate was evaporated to yield the title compound as
a yellow solid (0.2480 g, 0.685 mmol, 65%), Rf 0.52 (30%
4.1.6. 2-p-Toluenesulfanyl-[1,10]binaphthalenyl 11c.
t-BuLi (0.40 mL, 1.7 M solution in pentane, 2.10 equiv.,
0.681 mmol) 0was added dropwise at 278 8C to a solution of
2-bromo-[1,1 ]binaphthalenyl 7 (0.1076 g, 0.324 mmol) in
dry THF (4 mL) and stirred for 15 min under nitrogen. The
temperature was warmed to 220 8C to destroy the excess of
t-BuLi, and then decreased again to 278 8C. The reaction
was quenched with p-tolyl disulfide (0.1837 g, 2.30 equiv.,
0.745 mmol). The mixture was then left to warm to room
temperature, and a saturated solution of NH4Cl (5 mL) was
added. The two layers were separated; the organic phase
was washed with NaOH (2 M), dried over MgSO4 and
evaporated. The product sulfide was employed without
further purification.
81
EtOAc in petrol), mp 146–150 8C, m/z (EI) 364 (Mþ Br,
88%), 268 (100%), 239 (84%). Found Mþ 362.0308,
C21H15BrO requires Mþ 362.0307. nmax (CHCl3)/cm21
2930, 2838, 1620, 1588, 808, 745. dH (300 MHz, CDCl3):
8.08 (1H, d, J¼9.1 Hz), 7.96–7.88 (3H, m), 7.54–7.49 (2H,
m), 7.42–7.22 (5H, m), 7.06 (1H, d, J¼8.4 Hz), 3.85 (3H,
s). dC (75 MHz, CDCl3): 154.4, 134.8, 134.1, 133.0, 132.4,
130.0 (2CH), 129.1, 129.0, 128.0 (2CH), 126.8 (2CH),
126.3, 125.9, 124.6, 123.7, 123.3, 122.1, 113.8, 56.7.
4.1.5. (RS,P) and (RS,M)-2-Methoxy-20-(toluene-4-sulfi-
nyl)-[1,10]binaphthalenyl 12b. t-BuLi (1.76 mL, 1.7 M
solution in pentane, 2.10 equiv., 2.991 mmol) was added
dropwise at 278 8C to a solution of 20-bromo-2-methoxy-
[1,10]binaphthalenyl 9 (0.5157 g, 1.424 mmol) in dry THF
(15 mL) and stirred for 15 min under nitrogen. The reaction
was quenched with (2)-menthyl-(S)-p-toluene sulfinate
(0.9647 g, 2.30 equiv., 3.276 mmol) dissolved in THF
(10 mL). The mixture was left to warm to room temperature,
and a saturated solution of NH4Cl (10 mL) was added. The
layers were separated, and the organic phase was washed
with sat. NH4Cl, dried over MgSO4 and evaporated. The
crude product was purified by flash chromatography with
eluent petrol/EtOAc (4:1) to give a mixture of two
diastereoisomers of the title compound; this mixture
afforded separately the two diastereoisomers by repeated
fractional crystallisation from EtOAc (Diastereoisomer A
0.4418 g, 35%; Diastereoisomer B 0.3913 g, 31%). Com-
pounds 12b show nmax (CHCl3)/cm21 2926, 2842, 1621,
1593, 1508, 1046 (SvO), 809, 747, 731; m/z (EI) 422 (M,
5%), 318 (49%), 268 (100%). Found Mþ 422.1335,
C28H22O2S requires Mþ 422.13404.
4.1.7. (RS,P) and (RS,M)-2-(Toluene-4-sulfinyl)-
[1,100]binaphthalenyl 12a. (a) By lithiation of 2-bromo-
[1,1 ]binaphthalenyl 7 and reaction with (2)-menthyl-(S)-p-
toluene sulfinate. t-BuLi (1.12 mL, 1.7 M solution in
pentane, 2.10 equiv., 1.897 mmol) was added dropwise at
278 8C to a solution of 2-bromo-[1,10]binaphthalenyl 7
(0.3000 g, 0.904 mmol) in dry THF (10 mL) and the
mixture was stirred for 15 min under nitrogen. The reaction
was quenched with (2)-menthyl-(S)-p-toluene sulfinate11
(0.6119 g, 2.30 equiv., 2.079 mmol) dissolved in THF
(10 mL). The mixture was allowed to warm to room
temperature, and a saturated solution of NH4Cl (20 mL) was
added. The layers were separated, the organic phase was
washed with sat. NH4Cl, dried over MgSO4 and evaporated.
Purification by flash chromatography with eluent petrol/
EtOAc (4:1) gave a mixture of two diastereoisomers of the
title compound (0.0338 g, 0.086 mmol, 10%). Analytical
HPLC was carried out with Sphereclone column, flow
0.5 mL/min, at room temperature in hexane/IPA (95:5), tr
16.32 min (60.4%) and 17.01 min (39.6%). Small samples
(ca. 2 mg) of each diastereoisomer were obtained by
preparative HPLC.
Diastereoisomer A, colourless needles, shown by X-ray
crystallography to be P-12b, mp 218–221 8C, Rf 0.30 (40%
EtOAc in petrol); dH (300 MHz, CDCl3): 8.07 (1H, d,
J¼8.8 Hz), 8.00 (1H, d, J¼8.8 Hz), 7.93 (1H, d, J¼9.1 Hz),
7.82 (1H, d, J¼8.4 Hz), 7.78 (1H, d, J¼8.2 Hz), 7.43–7.37
(1H, m), 7.27–7.17 (5H, m), 7.15 (1H, d, J¼9.1 Hz), 7.12
(2H, d, J¼8.0 Hz), 7.01 (2H, d, J¼8.0 Hz), 3.28 (3H, s),
2.20 (3H, s); dC (75 MHz, CDCl3): 154.8, 142.3, 142.0,
140.9, 134.6, 134.3, 133.5, 132.5, 131.0, 129.7, 129.3,
128.7, 128.3, 128.0, 127.6, 127.0, 126.4, 125.9, 124.5,
124.0, 120.6, 117.1, 112.0, 55.2, 21.3.
(b) By oxidation of 2-p-tolylsulfanyl-[1,10]binaphthalenyl
(7) with m-CPBA. A 75% solution of m-chloroperoxy-
benzoic acid (0.1099 g, 1.00 equiv., 0.478 mmol) was added
to a solution of 2-p-tolylsulfanyl-[1,10]binaphthalenyl 11c
(0.1796 g, 0.478 mmol) in DCM (5 mL). The reaction
mixture was stirred at room temperature for 2 h, washed
with a solution of NaHCO3, dried over MgSO4 and
evaporated. Purification by flash chromatography with
eluent petrol/EtOAc (19:1) gave the title compound as a
mixture of two diastereoisomers (0.0125 g, 0.032 mmol,
7%). Analytical HPLC was carried out with Sphereclone
column, flow 0.5 mL/min, at room temperature in hexane/
IPA (95:5), tr 16.25 min (53.9%) and 16.99 min (46.1%).
Compounds 12a show Rf 0.24 (30% EtOAc in petrol), m/z
(EI) 392 (M, 49%), 269 (100%), 49 (84%). Found Mþ
392.1235, C27H20OS requires Mþ 392.1235. nmax (CHCl3)/
cm21 2921, 2852, 1044 (SvO), 805, 781.
Diastereoisomer B, colourless needles, shown by X-ray
crystallography to be M-12b, mp 208–212 8C, Rf 0.23 (40%
EtOAc in petrol); dH (300 MHz, CDCl3): 8.23 (1H, d,
J¼8.7 Hz), 8.07 (1H, d, J¼8.8 Hz), 7.98 (1H, d, J¼9.1 Hz),
7.86 (1H, d, J¼8.1 Hz), 7.73 (1H, d, J¼8.2 Hz), 7.43 (1H, d,
J¼9.1 Hz), 7.43 (1H, t, J¼8.1 Hz), 7.21–7.10 (3H, m),
6.76–6.71 (1H, m), 6.64 (2H, d, J¼8.2 Hz), 6.60 (2H, d,
J¼8.4 Hz), 6.16 (1H, d, J¼8.5 Hz), 3.84 (3H, s), 2.04 (3H,
s); dC (75 MHz, CDCl3): 154.5, 141.2, 140.8, 134.5, 133.6,
Diastereoisomer A. dH (300 MHz, CDCl3): 8.29 (1H, d,
J¼8.7 Hz), 8.19 (1H, d, J¼8.8 Hz), 8.06 (1H, dd, J¼7.5,
1.7 Hz), 7.99 (1H, d, J¼8.2 Hz), 7.92 (1H, d, J¼8.2 Hz),

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J. Clayden et al. / Tetrahedron 60 (2004) 4387–4397
7.75–7.68 (2H, m), 7.59–7.53 (1H, m), 7.43–7.37 (1H, m),
7.34–7.28 (1H, m), 7.21 (1H, d, J¼8.7 Hz), 6.95 (1H, ddd,
J¼8.2, 6.9, 1.2 Hz), 6.80 (2H, d, J¼8.4 Hz), 6.75 (2H, d, J¼
8.1 Hz), 6.53 (1H, d, J¼8.5 Hz), 2.16 (3H, s).
(300 MHz, CDCl3): 8.13 (2H, d, J¼8.7 Hz), 7.99 (2H, d,
J¼8.1 Hz), 7.67–7.59 (4H, m), 7.49–7.44 (2H, m), 7.33
(2H, d, J¼8.1 Hz), 7.24 (4H, d, J¼8.4 Hz), 7.16 (4H, d,
J¼8.1 Hz), 2.36 (6H, s). dC (75 MHz, CDCl3): 142.2, 141.3,
140.4, 136.7, 135.0, 133.0, 131.7, 130.4, 130.0, 129.7,
129.1, 128.5, 128.4, 127.8, 126.3, 126.0, 21.6.
Diastereoisomer B. dH (300 MHz, CDCl3): 8.29 (1H, d, J¼
8.7 Hz), 8.19 (1H, d, J¼8.8 Hz), 8.07–7.98 (3H, m), 7.58–
7.55 (3H, m), 7.50–7.27 (5H, m), 7.18 (2H, d, J¼8.1 Hz),
7.03 (2H, dd, J¼7.5, 1.1 Hz), 2.37 (3H, s).
Diastereoisomer B: mp 81–85 8C, Rf 0.15 (petrol/EtOAc
2:3); dH (300 MHz, CDCl3): 8.48 (2H, d, J¼8.8 Hz), 8.20
(2H, d, J¼8.8 Hz), 7.80 (2H, d, J¼8.2 Hz), 7.28 (2H, t, 7.2),
6.70–6.64 (2H, m), 6.54 (4H, d, J¼8.2 Hz), 6.46 (4H,
d, J¼8.2 Hz), 6.06 (2H, d, J¼8.5 Hz), 1.96 (6H, s). dC
(75 MHz, CDCl3): 142.8, 141.8, 140.7, 134.3, 132.5, 131.0,
130.3, 129.4, 128.4, 127.2, 127.1, 126.3, 125.9, 119.9, 21.4.
4.1.8. (RS,P) and (RS,M)-20-Bromo-2-(toluene-4-sulfinyl)-
[1,10]binaphthalenyl 12c. t-BuLi (0.63 mL, 1.7 M solution
in pentane, 2.10 equiv., 1.076 mmol) was added dropwise at
278 8C to a solution of 2,20-dibromo-[1,10]-binaphthalenyl
6 (0.2100 g, 0.512 mmol) in dry THF (5 mL) and stirred for
15 min under nitrogen. (2)-Menthyl-(S)-p-toluene sulfi-
nate11 (0.3469 g, 2.30 equiv., 1.178 mmol) dissolved in
THF (5 mL) was added. The mixture was left to warm to
room temperature, and a saturated solution of NH4Cl
(10 mL) was added. The layers were separated, the organic
phase was washed with sat. NH4Cl, dried over MgSO4 and
evaporated. Purification by flash chromatography with
eluent petrol/EtOAc (4:1) gave a mixture of two dia-
stereoisomers of the title compound (0.0975 g, 0.207 mmol,
40%). Separation of the diastereoisomers of 12c by flash
chromatography failed, but analytical HPLC carried out
with Sphereclone column, flow 0.5 mL/min, at room
temperature in hexane/IPA (9:1) showed tr 11.79 min
Also obtained were two diastereoisomers of bis-sulfoxide
14 as side products: diastereoisomer A (0.0351 g,
0.066 mmol, 13%) and diastereoisomer B (0.0239 g,
0.045 mmol, 9%).
4.1.10. (6)-2-Methoxy-20-methyl-[1,10]binaphthalenyl
11a.39 t-BuLi (1.7 M solution in pentane, 0.34 mL,
0.580 mmol, 2.10 equiv.) was added dropwise at 278 8C
to a solution of 2-bromo 7 (0.100 g, 0.276 mmol) in dry
THF (5 mL) and stirred for 15 min under nitrogen.
Iodomethane (0.09 mL, 1.381 mmol, 5.00 equiv.) was
added at 278 8C and the mixture allowed to warm to
room temperature. A saturated solution of NH4Cl (5 mL)
was added, and the two layers were separated; the organic
phase was washed with sat. NH4Cl, dried over MgSO4 and
evaporated under reduced pressure and without heating, to
give the title compound (0.0409 g, 50%) as a yellow solid,
m/z (EI) 298 (M, 100%), 268 (26%). Analytical HPLC was
carried out with Chiralpak OT (þ) column, flow 0.5 mL/
min, at 5 8C in methanol, tr 29.53 and 33.68 min. Spectro-
scopic data were consistent with the literature.39 dH
(300 MHz, CDCl3): 8.04 (1H, d, J¼9.1 Hz), 7.93 (2H, d,
J¼7.8 Hz), 7.91 (1H, d, J¼9.0 Hz), 7.56 (1H, d, J¼8.3 Hz),
7.51 (1H, d, J¼9.1 Hz), 7.45–7.35 (2H, m), 7.30–7.23 (2H,
m), 7.17 (1H, d, J¼8.4 Hz), 7.05 (1H, d, J¼8.5 Hz), 3.81
(3H, s), 2.15 (3H, s); dC (75 MHz, CDCl3): 154.7, 135.3,
133.9, 133.5, 132.6, 132.4, 129.8, 129.6–122.3 (12 Ar C),
114.1, 56.9, 20.6.
81
(58%) and 13.04 min (42%). m/z (EI) 473 (MHþþ Br,
33%), 268 (100%), 49 (87%). Found Mþ 470.0348,
C27H19BrOS requires Mþ 470.0340. nmax film/CHCl3
(cm21) 2922 (CH3), 1581, 1500 (two Ar C–C bands),
1044 (SvO), 809 (Ar C–H), 732 (C–Br); dH (300 MHz,
CDCl3): 8.42 (1H diast. A, d, J¼8.7 Hz), 8.31–8.25 (1H
diast. B, m), 8.22–6.71 (14H diast. Aþ15H diast. B, m),
6.28 (1H diast. A, d, J¼8.4 Hz), 2.38 (3H diast. B, s), 2.16
(3H diast. A, s).
4.1.9. (RS,RS,P) and (RS,RS,M)-2,20-Bis-(toluene-4-sulfi-
nyl)-[1,10]binaphthalenyl 14. t-BuLi (2.30 mL, 1.7 M
solution in pentane, 4.00 equiv., 3.903 mmol) was added
dropwise at 278 8C to a solution of 2,20-dibromo-
[1,10]binaphthalenyl 9 (0.4000 g, 0.976 mmol) in dry THF
(10 mL) and stirred for 15 min under nitrogen. The reaction
mixture was then allowed to reach a temperature of about
220 8C, and added via cannula to a flask containing
(2)-menthyl-(S)-p-toluene sulfinate11 (0.7183 g, 2.50 equiv.,
2.440 mmol) dissolved in THF (10 mL). The mixture was
allowed to warm to room temperature, and a saturated
solution of NH4Cl (20 mL) was added. The layers were
separated, the organic phase was washed with saturated
NH4Cl, dried over MgSO4 and evaporated. Purification by
flash chromatography with eluent petrol/EtOAc (4:1 to 1:1)
gave the two diastereoisomers of the title compound:
diastereoisomer A (0.1771 g, 0.334 mmol, 34%), and
diastereoisomer B (0.1485 g, 0.280 mmol, 29%). m/z (EI)
531 (M, 3%), 268 (100%), 49 (64%). Found Mþ 531.1449,
C34H26O2S2 requires Mþ 530.13741. nmax (CHCl3)/cm21
296, 2923 (two CH3 bands), 1464 (CH3), 1044 (SvO), 809
(Ar C–H).
4.1.11. (M)-2-Methoxy-20-methyl-[1,10]binaphthalenyl
M-11a. In a similar way, P-12b (0.0864 g) gave M-11a,
0.0509 g, 83%, with .99% ee [Chiralpak OT (þ)].
4.1.12. (P)-2-Methoxy-20-methyl-[1,10]binaphthalenyl
P-11a. In a similar way, M-12b (0.0780 g) gave P-11a,
0.0390 g, 71%, with .99% ee [Chiralpak OT (þ)].
4.1.13. (6)-2-Methoxy-[1,10]binaphthalenyl (6)-11b.40 In
a similar way, but quenching with NH4Cl instead of MeI,
bromonaphthalene 7 (0.0894 g, 0.247 mmol) gave, after
work up and evaporation under reduced pressure and
without heating, the title compound as a yellow solid,
0.0542 g, 77%, Rf 0.30 (5% EtOAc in petrol). Analytical
HPLC was carried out with Chiralpak OT (þ) column, flow
0.7 mL/min, at 5 8C in methanol, tr 25.63 and 29.61 min.
Spectroscopic data were consistent with the literature.40 dH
(300 MHz, CDCl3): 8.01 (2H, t, J¼9.1 Hz), 7.99 (1H, d,
J¼9.2 Hz), 7.92 (1H, d, J¼8.1 Hz), 7.66 (1H, dd, J¼8.2,
Diastereoisomer A, identified by X-ray crystal structure as
P-14: mp 248–252 8C, Rf 0.28 (petrol/EtOAc 2:3); dH

J. Clayden et al. / Tetrahedron 60 (2004) 4387–4397
4395
7.0 Hz), 7.51–7.47 (3H, m), 7.38–7.21 (5H, m), 2.22
(3H, s).
chromatography (EtOAc/petroleum ether (bp 40–60 8C)
1:3) gave the sulfoxide P-17 as a white solid (95 mg, 95%).
4.1.14. (M)-2-Methoxy-[1,10]binaphthalenyl M-11b
(enantiomer A). In a similar way, P-12b (0.0383 g,
0.091 mmol) gave M-11b, 0.0111 g, 43%, 97% ee [Chiral-
pak OT (þ)].
4.1.15. (P)-2-Methoxy-[1,10]binaphthalenyl P-11b (enan-
tiomer B). In a similar way, M-12b (0.0231 g, 0.055 mmol)
gave P-11b, 0.0081 g, 52%, 81% ee [Chiralpak OT (þ)].
4.1.17. (M)-8-Methoxynaphthalene-1-carboxylic acid
diisopropylamide M-15. t-Butyllithium (1.5 equiv.) was
added to sulfoxide P-17 (40 mg, 0.1 mmol) in THF (5 mL)
at 278 8C under nitrogen. After 24 h at this temperature,
saturated ammonium chloride solution was added, and the
mixture was extracted with CH2Cl2, washed with brine,
dried over MgSO4 and evaporated under reduced pressure.
Purification by column chromatography [EtOAc/petroleum
ether (bp 40–60 8C) 1:3] yielded M-15 as a white solid
(29 mg, 100%).35 The enantiomeric excess was determined
by HPLC on a chiral column (Whelk-O1) and was found to
be greater than 99%.
4.1.16. (RS,P) and (RS,M)-8-Methoxy-2-(toluene-4-sulfi-
nyl)-naphthalene-1-carboxylic acid diisopropylamide
17. sec-Butyllithium (1.3 equiv.) was added to naphthamide
1535 (0.7 g) dissolved in dry THF (10 mL) at 278 8C under
nitrogen atmosphere. A light green colour appeared after
10 min, and after 2 h (2)-menthyl (S)-p-toluenesulfinate11
(1.5 equiv.) was added. After 24 h at 278 8C the reaction
mixture was allowed to warm slowly to room temperature
and quenched with saturated NH4Cl. The organic layer was
extracted with CH2Cl2, washed with brine, dried over
MgSO4 and evaporated under reduced pressure. Purification
by column chromatography (EtOAc/petroleum ether
(40–60 8C) 1:3 then 1:1 to obtain diastereoisomer A, then
using EtOAc/DCM 1:1 in order to collect polar diastereo-
isomer B) gave two diastereoisomers in 1:1 ratio [0.43 g
(41%) and 0.42 g (40%)].
4.1.18. (6)-2-Diphenylphosphanyl-8-methoxy-naph-
thalene-1-carboxylic acid diisopropylamide (6)-18
(R5PPh2). Amide 15 (1 g, 3.51 mmol) was dissolved in
15 mL of degassed THF under nitrogen atmosphere at
278 8C. sec-Butyllithium (1.2 equiv.) was added dropwise
to the reaction mixture. The brown-orange solution was
stirred at 278 8C for 2 h. Chlorodiphenylphosphine
(2 equiv., 7.02 mmol) was added dropwise to the solution,
and after a further 24 h at 278 8C the mixture was allowed
to warm to RT, poured through celite and concentrated
under reduced pressure. Flash chromatography (EtOAc/
petroleum ether (bp 40–60 8C) 1:7) gave the phosphine
(^)-18 (R¼PPh2) as a white solid (1.15 g, 70%); Rf
[EtOAc/petroleum ether (bp 40–60 8C), 1:1] 0.67; dH
(300 MHz; CDCl3) 7.70 (1H, d, J¼8 Hz, ArH), 7.40
(13H, m, ArH), 6.92 (1H, d, J¼7 Hz, ArH), 3.96 (3H, s,
OCH3), 3.64 [2H, 2 septets, J¼7 Hz, NCH(CH3)2], 1.82
[3H, d, J¼7 Hz, NCH(CH3)2], 1.76 [3H, d, J¼7 Hz,
NCH(CH3)2], 1.15 [3H, d, J¼6 Hz, NCH(CH3)2], 1.05
[3H, d, J¼6 Hz, NCH(CH3)2]; m/z (CI) 470 (80%,
(MþH)þ), (EI) 470 (5%, (MþH)þ); Found (EI): (MþH)þ,
470.2248, C30H32NPO4 requires (MþH)þ 470.2249.
Diastereoisomer A, shown by X-ray crystallography to be
P-17: mp 117–119 8C; Rf [EtOAc/petroleum ether (bp 40–
60 8C), 1:1] 0.08; [a]2D3 2212.3 (c¼1.25, CDCl3); nmax
(film)/cm21 2970(CH), 1628 (CvO); dH (300 MHz,
CDCl3) 7.85 (1H, d, J¼9 Hz, ArH), 7.50 (5H, m, ArH),
7.27 (2H, d, J¼9 Hz, ArH), 7.00 (1H, d, J¼10 Hz, ArH),
4.00 (3H, s, OCH3), 3.59 [2H, 2 septets, J¼7 Hz,
NCH(CH3)2], 2.44 (3H, s, ArCH3), 1.75 [6H, dd, J¼7,
10 Hz, NCH(CH3)2], 1.08 [3H, d, J¼7 Hz, NCH(CH3)2],
0.94 [3H, d, J¼7 Hz, NCH(CH3)2]; dC (CDCl3) 166.7
(CvO), 156.4, 141.6, 140.9, 138.7, 136.7, 136.5, 129.8,
129.6, 128.9 (£2), 126.3 (£2), 124.1, 121.0, 120.8, 107.3,
55.4, 50.7, 46.5, 21.3, 21.0, 20.4, 20.3, 19.6; m/z (CI) 424
(90%, (MþH)þ), (EI) 424 (15%, MþHþ); Found (EI): Mþ,
423.1870, C25H29NO3S requires M, 423.1868.
4.1.19. (2)-2-Diphenylphosphanyl-8-methoxynaph-
thalene-1-carboxylic acid diisopropylamide (2)-18
(R5PPh2).29 (a) From M-15. By the method reported for
(^)-18, M-15 (100 mg, 3.51 mmol) gave phosphine (2)-18
(115 mg, 70%) as a white solid, mp 207–209 8C (lit.29 209–
211 8C) [a]2D3 275.8 (c¼0.25, CHCl3); Rf [EtOAc/petro-
leum ether (bp 40–60 8C), 1:1] 0.67; dH (300 MHz; CDCl3)
7.70 (1H, d, J¼8 Hz, ArH), 7.40 (13H, m, ArH), 6.92 (1H,
d, J¼7 Hz, ArH), 3.96 (3H, s, OCH3), 3.64 [2H, 2 septets,
J¼7 Hz, NCH(CH3)2], 1.82 [3H, d, J¼7 Hz, NCH(CH3)2],
1.76 [3H, d, J¼7 Hz, NCH(CH3)2], 1.15 [3H, d, J¼6 Hz,
NCH(CH3)2], 1.05 [3H, d, J¼6 Hz, NCH(CH3)2]; m/z (CI)
470 (80%, (MþH)þ), (EI) 470 (5%, (MþH)þ); Found (EI):
(MþH)þ, 470.2248, C30H32NPO4 requires (MþH)þ
470.2249. Enantiomeric excess was determined by HPLC
(Whelk-O1) and was found to be greater than 95%.
Diastereoisomer B M-17): mp 200–201 8C; Rf [EtOAc/
petroleum ether (bp 40–60 8C), 1:1] 0.53; [a]2D3 2305.2
(c¼0.85, CDCl3); nmax (film)/cm21 2972 (CH), 1629
(CvO); dH (300 MHz, CDCl3) 7.80 (4H, m, ArH), 7.45
(2H, m, ArH), 7.25 (2H, d, J¼8 Hz, ArH), 6.98 (1H, d,
J¼8 Hz, ArH), 4.02 (3H, s, OCH3), 3.65 [2H, 2£ septet,
J¼7 Hz, NCH(CH3)2], 2.37 (3H, s, ArCH3), 1.80 [6H, d,
J¼7 Hz, NCH(CH3)2], 1.31 [3H, d, J¼7 Hz, NCH(CH3)2],
1.12 [3H, d, J¼7 Hz, NCH(CH3)2]; dC (CDCl3) 168.0
(CvO), 156.1, 141.9, 140.7, 140.3, 136.1, 133.3, 130.0,
129.6, 128.5, 124.4, 121.3, 121.0, 120.2, 106.8, 55.2, 51.3,
46.3, 21.2, 20.8, 20.4, 20.2, 19.6; m/z (EI) 423 (5%, Mþ);
Found (EI): Mþ, 423.1860, C25H29NO3S requires M,
423.1868.
(b) By direct sulfoxide lithium exchange: t-Butyllithium
(1.5 equiv.) was added to sulfoxide P-17 (40 mg, 0.1 mmol)
in degassed THF (5 mL) at 278 8C under nitrogen. After
10 min freshly distilled chlorodiphenylphosphine was
added. The mixture was stirred for a further 24 h at
278 8C, allowed to warm to RT, poured through celite and
evaporated under reduced pressure. Flash chromatography
Equilibration of the diastereoisomeric sulfoxides. Sulfoxide
M-17 (100 mg) was heated in toluene at 100 8C for 12 h.
The solvent was evaporated under reduced pressure. Flash

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J. Clayden et al. / Tetrahedron 60 (2004) 4387–4397
(EtOAc/petroleum ether (bp 40–60 8C) 1:7) gave the
phosphine (2)-18 as a white solid (27 mg, 60%); [a]D23
277.6 (c¼0.5, CHCl3). The enantiomeric excess was
determined by HPLC on a chiral column (Whelk-O1) and
was found to be greater than 95%.
J¼6 Hz, NCH(CH3)2], 3.12(1H, s, ArCH2R), 3.10 (1H, s,
ArCH2R), 2.40 [1H, m, CH2COH(CH2)2CH2], 2.30 [1H, m,
CH2COH(CH2)2CH2], 2.00 [2H, m, CH2COH(CH2)2CH2],
1.72 [8H, m, NCH(CH3)2 and CH2COH(CH2)2CH2], 1.00
[6H, m, NCH(CH3)2]; dC (CDCl3) 173.3 (CvO), 155.2,
134.1, 133.2, 132.2, 129.4, 128.3, 126.7, 126.3, 121.7,
121.2, 106.2, 74.8, 55.6, 51.3, 45.5, 42.0, 39.1, 34.7, 20.9,
20.8, 20.6, 19.5; m/z (CI) 370 (100%, (MþH)þ), (EI) 470
(10%, (MþH)þ); Found (EI): (M)þ, 369.2290, C23H31NO3
requires (M)þ 369.2304.
4.1.20. (6)-8-Methoxy-2-methyl-naphthalene-1-carb-
oxylic acid diisopropylamide (6)-19. Amide 15 (1.00 g,
3.51 mmol) was dissolved in 15 mL of THF under nitrogen
atmosphere at 278 8C. sec-Butyllithium (1.3 equiv.) was
added dropwise to the reaction mixture. The brown-orange
solution was stirred at 278 8C for 2 h and iodomethane
(2 equiv., 7.02 mmol) was added dropwise. After a further
1.5 h, saturated NH4Cl was added. The mixture was
extracted with CH2Cl2 (30 mL). The extracts were washed
with water, dried with MgSO4 and evaporated under
reduced pressure. Flash chromatography (EtOAc/petroleum
ether (bp 40–60 8C) 1:3) gave the amide (^)-18 (R¼Me) as
a white solid (1.00 g, 95%); mp 223–224 8C; Rf [EtOAc/
petroleum ether (bp 40–60 8C), 1:1] 0.36; nmax (film)/cm21
2963 (CH), 1622 (CvO); dH (300 MHz; CDCl3) 7.60 (1H,
d, J¼8 Hz, ArH), 7.25 (3H, m, ArH), 6.76 (1H, d, J¼7 Hz,
ArH), 3.83 (3H, s, OCH3), 3.45 [2H, 2 septets, J¼7 Hz,
NCH(CH3)2], 2.41 (3H, s, ArCH3), 1.60 [6H, m,
NCH(CH3)2], 0.94 [6H, m, NCH(CH3)2]; dC (75 MHz;
CDCl3) 171.0 (CvO), 155.2, 133.5, 131.7 (£2), 129.4,
127.4, 125.3, 122.0, 120.8, 105.8, 55.2, 50.7, 45.7, 20.6,
20.5, 20.4, 19.7, 19.3; m/z (CI) 300 (100%, (MþH)þ), (EI)
299 (35%, Mþ); Found (EI): Mþ, 299.1893, C19H25NO2
requires M, 299.1885.
4.1.23. (2)-2-(1-Hydroxy-cylobutylmethyl)-8-methoxy-
naphthamide-1-carboxylic acid diisopropylamide
(2)-20. In a similar way, enantiomerically pure amide
(2)-19 (100 mg, 0.27 mmol) in THF (5 mL) gave, after
flash chromatography (EtOAc/petroleum ether (bp 40–
60 8C) 1:3) alcohol (2)-20 as a white solid (72 mg, 58%).
[a]2D3 296 (c¼0.2, CHCl3). ee .95% [HPLC, Whelk-O1].
Acknowledgements
We are grateful to the EPSRC and AstraZeneca for funding
(to P.M.K.), to Dr. Rudolf Schmid of Roche (Basel) for a
generous donation of 2,20-bisbromo-1,10-binaphthyl 6, and
to Dr. Madeleine Helliwell for determining the X-ray crystal
structures of P-12b, M-12b, P-14 and P-17.
References and notes
4.1.21. (2)-8-Methoxy-2-methylnaphthalene-1-carb-
oxylic acid diisopropylamide (2)-19. t-Butyllithium
(1.5 equiv.) was added to sulfoxide P-17 (40 mg,
0.1 mmol) in THF (5 mL) at 278 8C under nitrogen. After
10 min, methyl iodide was added, and after a further 2 h at
278 8C the mixture was allowed to warm to room
temperature. The product was extracted with DCM, washed
with brine, dried over MgSO4 and concentrated under
reduced pressure. Purification by flash chromatography
[EtOAc/petroleum ether (bp 40–60 8C) 1:3] yielded a white
solid (20 mg, 74%) [a]2D3 2106.6 (c¼0.2, CHCl3). The
enantiomeric excess was determined by HPLC on a chiral
stationary phase (Whelk-O1) and was found to be .99%.
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