Rapid, room-temperature acylative kinetic resolution of sec-alcohols using atropisomeric 4-aminopyridine/triphenylphosphine catalysis

Article abstract of DOI:10.1016/j.tet.2005.08.124

Two new atropisomeric 4-aminopyridine-based nucleophilic catalysts containing terphenyl 'blocking groups' have been prepared and evaluated for kinetic resolution (KR) of aryl alkyl sec-alcohols. One of these biaryls is shown to be the most selective atropisomeric catalyst yet prepared for several sec-alcohols but its low reactivity makes it non-optimal for use at room temperature (rt). Optimisation of the conditions for conducting KRs at rt using a previously described catalyst (containing a phenyl blocking group) at the 1 mol% level indicates that PPh₃ (1 equiv) is beneficial for enantioselectivity and allows KR of (±)-1-(naphthyl)ethanol in less than 30 min with s>15 (i.e., ～40% recovered alcohol with >95% ee). These conditions constitute a convenient and practical method for rapid KR of sec-alcohols and are anticipated to facilitate a detailed kinetic study of this catalytic manifold by calorimetry.

Full text of DOI:10.1016/j.tet.2005.08.124

Tetrahedron 62 (2006) 295–301
Rapid, room-temperature acylative kinetic resolution
of sec-alcohols using atropisomeric 4-aminopyridine/
triphenylphosphine catalysis
a,
a,†
*
Stellios Arseniyadis, Tomasz Fekner,
b,‡
Alan C. Spivey,
b,§
Adrian Maddaford and David P. Leese
b,§
a
Department of Chemistry, South Kensington Campus, Imperial College, London SW7 2AZ, UK
b
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
Received 16 May 2005; revised 29 July 2005; accepted 31 August 2005
Available online 7 November 2005
Abstract—Two new atropisomeric 4-aminopyridine-based nucleophilic catalysts containing terphenyl ‘blocking groups’ have been
prepared and evaluated for kinetic resolution (KR) of aryl alkyl sec-alcohols. One of these biaryls is shown to be the most selective
atropisomeric catalyst yet prepared for several sec-alcohols but its low reactivity makes it non-optimal for use at room temperature (rt).
Optimisation of the conditions for conducting KRs at rt using a previously described catalyst (containing a phenyl blocking group) at the
1
mol% level indicates that PPh (1 equiv) is beneficial for enantioselectivity and allows KR of (G)-1-(naphthyl)ethanol in less than 30 min
3
with sO15 (i.e., w40% recovered alcohol with O95% ee). These conditions constitute a convenient and practical method for rapid KR of
sec-alcohols and are anticipated to facilitate a detailed kinetic study of this catalytic manifold by calorimetry.
q 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
the vanguard of the contemporary ‘organocatalysis’
4
renaissance, and a number of attractive and practical KR
protocols for a range of sec-alcohols have resulted.
5
–9
The kinetic resolution (KR) of alcohols by enantioselective
esterification using small-molecule nucleophilic chiral
catalysts in combination with acid anhydrides or chlorides
has been studied by an increasing number of groups over the
Research from our laboratory has focused on the develop-
ment of axially chiral, atropisomeric derivatives of
4-aminopyridine and, in particular, 4-dialkylaminopyridines
2a and 2b (Scheme 1) as catalysts for the KR of
1
–3
past decade.
Indeed, this research area has been in
Scheme 1. Synthesis of catalysts 2a–d from triflates 1a and 1b. Reagents and conditions: For 2a and 2b see Refs. 11 and 12, respectively. For 2c and 1b:
(a) i. 3,5-diPh(C
6
H
a) 3,5-di-(3,5-diMeC
3
)Br, Mg, THF; ii. PdCl
H
2
(dppp) [23%]; (b) 3,5-diPh(C
6 3 2 2 2 3 4
H )B(OH) , Pd(OAc) , P(biph)Cy , LiCl, K PO , toluene [50%]. For 2d from 1b:
(
6
3
)C H B(OH) (3), P(biph)Cy
3
6
2
2
, LiCl, K PO , toluene [39%].
3
4
Keywords: Nucleophilic catalysis; Asymmetric catalysis; Organocatalysis; Atropisomerism; Esterification; Acylation; sec-Alcohols.
*
Corresponding author. Tel.: C44 20 759 45841; fax: C44 20 759 45833; e-mail: a.c.spivey@imperial.ac.uk
Current address: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Current address: Department of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland.
†
‡
§
Current address: Paekdale Molecular Ltd, Peakdale Science Park, Sheffield Road, Chapel-en-le-Frith, High Peak SK23 0PG, UK.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.124

296
A. C. Spivey et al. / Tetrahedron 62 (2006) 295–301
1
0,11
sec-alcohols.
A drawback to using these catalysts to
The synthesis of these two new catalysts 2c and 2d was
achieved from triflate 1b by either Kharasch or Suzuki-type
coupling of the appropriate terphenyl Grignard reagent or
boronic acid, respectively, followed by semi-preparative
CSP-HPLC (Scheme 1). The absolute configurations of the
atropisomeric axes were assigned using circular dichroism
date has been the requirement to conduct the experiments
for relatively long durations (typically w10 h) at low
temperature (K78 8C). We describe herein our endeavours
to achieve rapid KR at ambient temperature. This stemmed
from our desire to make the transformation more practical
on a process scale and to define conditions under which we
could conveniently study the detailed kinetics of such KR
processes by calorimetry.
1
1
spectroscopy (see Section 4).
Using the enantiomerically pure terphenyl catalysts 2c and
d, a series of KR experiments were performed with an
array of (G)-sec-alcohols 4a–f as substrates (Table 1).
2
2
. Results and discussion
To allow direct comparison with results obtained with
catalysts 2a and 2b, initial reactions were run at K78 8C in
toluene under previously optimised conditions with the
exception that acetic anhydride rather than isobutyric
During the course of our studies towards the development of
catalysts 2a and 2b, we prepared a related series of biaryls
having an N-methyl-5-azaindoline catalytic core in place of
1
0,12
1
2
anhydride was employed as acyl donor.
Preliminary
the 4-dialkylaminopyridine. Although this series of
compounds give modest levels of enantioselectivity relative
to 2b, it was found that the presence of a terphenyl group at
the 2-position of the naphthyl ring attached to the catalytic
core gave improved enantioselectivity relative to its phenyl
analogue. Reasoning that the improved stereoselectivity
reflected more efficient facial discrimination between the
front and back faces of the pyridine ring leading to increased
studies revealed that this led to higher levels of stereo-
selectivity across the board (e.g., sZ39 vs sZ17,
respectively, for the use of catalyst 2c with alcohol 4c,
entries 3 and 5; other data not shown). It can be seen that,
despite their similar structures, terphenyl-containing cata-
lyst 2c is significantly more stereoselective than terphenyl-
containing catalyst 2d despite their similar structures.
Catalyst 2c is more stereoselective than phenyl-containing
catalysts 2a and 2b for alcohols 4a, 4c and 4d and similarly
selective for the other alcohols. The rates of reactions
catalysed by terphenyl-containing catalysts 2c and 2d are,
however, lower by a factor of w2 as compared to those
catalysed by phenyl-containing catalysts 2a and 2b.
#
DDG between the diastereomeric transition states for
esterification, we were keen to investigate the performance
of terphenyl-containing catalysts 2c and 2d relative to the
parent compound 2b. In particular, we were hopeful that
these catalysts might allow for good levels of selectivity in
KRs run at ambient temperature.
Table 1. KR of alcohols 4a–f using enantiomerically pure biaryls 2c and 2d
a
b
s
ref c
(s )
Entry
Cat.
Alcohol, ester
4, 5
Anhydride Time (h)
0
(S)-4
ee (%)
(R)-5
ee (%)
C (%)
d
e
Ar, R
R
A
E
f
1
2c
2c
2c
2c
2c
2c
2c
2c
2d
2d
2d
2d
4a, 5a
4b, 5b
4c, 5c
4c, 5c
4c, 5c
4d, 4d
4e, 5e
4f, 5f
4a, 5a
4c, 5c
4d, 4d
4f, 5f
Ph, Me
Ph, Et
1-Nap, Me
1-Nap, Me
1-Nap, Me
Me
Me
Me
Me
i-Pr
Me
Me
Me
Me
Me
Me
Me
6.0
9.0
6.6
11.3
8.2
6.6
6.6
7.0
6.7
6.8
6.2
6.2
5.7
17.1
16.8
94.2
11.6
21.5
5.8
13.7
4.5
10.6
6.2
90.3
83.2
94.1
76.9
87.8
92.3
90.8
89.9
73.1
85.1
82.1
72.8
6
17
15
55
12
19
6
13
6
11
7
22
13
39
27
17
31
22
22
(13)
(13)
(29)
2
3
4
g
f
5
f
6
2-MeC
6 4
2-MeOC H
6
H
4
, Me
, Me
, Me
(25)
(25)
(25)
7
8
9
2,6-diMeC
Ph, Me
1-Nap, Me
6
H
3
f
6.7
14
11
f
10
11
12
2-MeC
6
H
4
, Me
, Me
2,6-diMeC
6
H
3
3.8
5
6.5
a
b
c
d
e
f
Conversion CZ100!ee
Selectivity factor reproducible to G2 in parallel runs.
A
/(ee
A E
Cee ).
13
i
The s values in parentheses are those obtained for this substrate using catalyst 2b with ( PrCO)
2
O (taken from Ref. 11).
ee Of recovered alcohol, established by CSP-HPLC.
ee Of ester, established by CSP-HPLC on derived alcohol following saponification.
The dextrorotatory enantiomer of catalyst was employed giving enantiomeric products to those shown.
g
2
Ac O (2.5 equiv) used.

A. C. Spivey et al. / Tetrahedron 62 (2006) 295–301
297
The modest increase in stereoselectivity and significant
decrease in reactivity displayed by terphenyl-containing
catalyst 2c relative to phenyl-containing catalyst 2b
persuaded us to focus further studies on the more readily
prepared and resolved catalyst 2b. Our aim was to find
optimal conditions for running rapid KR reactions with this
catalyst at ambient temperature. Using (G)-1-(naphthy-
l)ethanol 4c as a test substrate and isobutyric anhydride
reactions carried out using P4-t-Bu phosphazine base
(entries 12 and 13), all the reactions reached completion
and, although the levels of stereoselectivity did not
vary dramatically, the use of 2,6-di-t-butyl pyridine gave
the most stereoselective KRs in both solvent systems
(entries 14 and 15).
In order to determine the performance of these optimised
conditions for KR at rt we conducted a larger scale KR of
(G)-1-(naphthyl)ethanol 4c using 1.0 rather than 0.5 equiv
of isobutyric anhydride and removed aliquots for analysis
by CSP-HPLC every 2 min (to 10 min), every 5 min (to
45 min) and at increasing intervals thereafter (to 20 h;
Graphs 1 and 2) (Scheme 2).
(
0.5 equiv) as acyl donor we first surveyed the influence of
the reaction solvent and auxiliary base on the KR process
Table 2).
(
Solvent screening (entries 1–7) in the absence of an
auxiliary base revealed that the reactions conducted in
1
4
t-amyl alcohol (t-AmOH) and toluene (entries 1 and 2)
reached completion (i.e., Cw50%, as limited by the amount
of anhydride present) within 1 h and gave the highest levels
of stereoselectivity. The reactions also reached completion
in cyclohexane and THF but the stereoselectivities were
reduced (entries 3 and 4). The reactions did not reach
completion in DMF, CH Cl , or DMPU and, additionally,
The data show that the reaction reaches w60% conversion
in w25 min under these conditions, and that at this point
the ee of the recovered starting material is O95%.
Finally, we surveyed a number of achiral additives in
1
6
order to optimise the selectivity further. The reactions
were performed using 0.5 equiv of isobutyric anhydride,
2
2
gave poor levels of enantioselectivity (entries 5–7).
0.5 equiv of 2,6-di-t-butyl pyridine and 1 equiv of the
additive in both t-amyl alcohol and toluene (Table 3).
Using both t-AmOH and toluene as solvents, Et N, pyridine,
3
P4-t-Bu phosphazine [Schwessinger’s base, t-BuN]P-
1
N]PNMe ) ], 2,6-di-t-butylpyridine, 1,2,2,6,6-penta-
5
(
methylpiperidine (PMP), K CO and K PO were surveyed
Surprisingly, given that Sc(OTf) has been reported to act
3
2
3
synergistically with 4-DMAP to accelerate esterification
reactions, this additive completely inhibited the reaction
2
3
3
4
1
7
as auxiliary bases (entries 8–21). With the exception of the
Table 2. Effect of the solvent and auxiliary base on the KR of alcohol 4c using catalyst 2b
a
b
s
Entry
Base
Solvent
(S)-4c
(R)-5c
C (%)
c
d
ee
A
(%)
E
ee (%)
1
2
3
4
5
6
7
8
9
None
t-AmOH
Toluene
Cyclohexane
THF
72.8
68.4
46.0
52.0
31.0
47.2
16.0
71.8
69.7
67.4
64.0
22.6
10.4
79.8
71.0
80.0
69.0
63.4
62.6
73.6
68.0
70.6
68.6
45.4
56.0
39.0
63.6
34.0
70.8
63.7
72.2
66.6
46.6
17.2
69.2
68.4
69.0
65.2
73.8
66.4
71.0
65.6
51
50
50
48
44
43
32
50
52
48
49
33
38
54
51
54
51
46
49
51
51
12.6
10.8
4.1
5.8
3.0
7.1
2.4
12.2
9.1
12.2
9.5
3.4
1.6
13.5
11.1
13.3
9.5
12.5
9.4
DMF
CH Cl
DMPU
2
2
NEt
3
t-AmOH
Toluene
t-AmOH
Toluene
t-AmOH
Toluene
t-AmOH
Toluene
t-AmOH
Toluene
t-AmOH
Toluene
t-AmOH
Toluene
10
11
12
13
14
15
16
17
18
19
20
21
Pyridine
P4-t-Bu-Phosphazene
2,6-di-(t-Bu)-Pyridine
1,2,2,6,6-PMP
K
K
2
CO
3
3
PO
4
12.8
9.6
a
b
c
d
A A E
Conversion CZ100!ee /(ee Cee ).
13
Selectivity factor reproducible to G1 in parallel runs.
ee Of recovered alcohol, established by CSP-HPLC.
ee Of ester, established by CSP-HPLC on derived alcohol following saponification.

298
A. C. Spivey et al. / Tetrahedron 62 (2006) 295–301
100
80
60
40
20
0
ee (4c)
Conversion (%)
0
200
400
600
800
1000 1200 1400
Time (min)
Graph 1. ee Of 4c and % conversion versus time.
100
80
60
40
20
0
ee (5c)
Conversion (%)
0
200
400
600
800
1000
1200
1400
Time (min)
Graph 2. ee Of 5c and % conversion versus time.
1) (i-PrCO)2O (0.5 equiv.)
base (0.5 equiv.)
cat. (>99.8% ee, 1 mol%)
solvent, rt, 1 h
OH
OH
OCOi-Pr
NEt2
N
Ph
+
2
) MeOH
(-)-(Sa)-2b
(
–)-4c
(S)-4c
(R)-5c
cat.
Scheme 2.
˚
in both solvents (entries 1 and 2). The presence of 4 A
molecular sieves appeared to have no effect on the reaction
3. Conclusions
(
entries 3 and 4) and n-Bu NBr, 1-hydroxypyridine and
4
Two approaches towards the development of efficient
conditions for the rapid acylative KR of aryl alkyl
sec-alcohols using atropisomeric 4-aminopyridine-based
nucleophilic catalysts have been explored. Two new
catalysts, 2c and 2d, containing terphenyl ‘blocking groups’
have been prepared and evaluated for this purpose. Catalyst
2c was found to be more enantioselective than 2d, and is the
most selective atropisomeric catalyst yet described for KR
of several sec-alcohols. The low reactivity of this catalyst,
however, militates against its use for rapid KR at rt.
Optimisation of the conditions for conducting KRs at rt
using previously described catalyst 2b at the 1 mol% level
HMPA were deleterious to the levels of selectivity in both
solvents (entries 5–10). However, a small but reproducible
increase in selectivity was observed in both solvents when
using PPh as an additive giving a selectivity of 15.5 in
3
t-amyl alcohol and 13.5 in toluene (entries 11 and 12)
compared to 13.5 and 11.1, respectively, when no additive
was used (Table 2, entries 14 and 15). However, use of
P(O)Ph , PEt , P(4-FC H ) , AsPh or BiPh in place of the
PPh3 did not promote similar or further increases in
stereoselectivity (entries 13–20).
3
3
6
4 3
3
3
Although the role of the PPh is not clear at this time, its use
3
indicate that PPh (1 equiv) is beneficial for selectivity and
3
in conjunction with 2,6-di-t-butyl pyridine/t-amyl alcohol
allows for significantly more stereoselective KRs than under
the conditions used as a starting point for this investigation
allows KR of (G)-1-(naphthyl)ethanol 4c to occur in
!30 min to give w40% recovered alcohol with O95% ee
(i.e., sw15). This rapid KR process is expected to facilitate
detailed kinetic studies by calorimetry; studies that we hope
(
cf. Table 3, entry 11, sZ15.5 and Table 2, entry 9, sZ9.1).

A. C. Spivey et al. / Tetrahedron 62 (2006) 295–301
Table 3. Effect of some additives on the KR of alcohol 4c using catalyst 2b
299
a
b
s
Entry
Additive
Solvent
(S)-4c
(R)-5c
C (%)
c
d
ee
A
(%)
E
ee (%)
1
2
3
4
5
6
7
8
9
Sc(OTf)
3
t-AmOH
Toluene
t-AmOH
Toluene
t-AmOH
Toluene
t-AmOH
Toluene
t-AmOH
Toluene
t-AmOH
Toluene
t-AmOH
Toluene
t-AmOH
Toluene
t-AmOH
Toluene
Toluene
Toluene
—
—
—
—
—
—
50
52
50
50
47
47
52
50
53
54
50
49
53
50
51
49
47
54
—
—
13.3
11.4
9.1
7.4
9.6
5.8
˚
MS (4 A)
73.8
74.6
64.2
61.4
61.6
50.2
76.2
65.4
81.4
82.4
71.0
66.0
74.4
62.2
69.2
57.4
64.2
74.0
72.4
68.0
65.2
60.6
68.0
56.4
69.0
64.0
72.4
69.2
70.1
68.4
66.0
63.4
66.3
59.8
71.0
62.0
4
n-Bu NBr
2-Hydroxypyridine
HMPA
11.1
8.6
10
11
12
13
14
15
16
17
18
19
20
PPh
P(O)Ph
AsPh
BiPh
3
15.5
13.5
12.3
10.5
10.6
7.9
10.0
7.0
11.1
9.0
3
3
3
PEt
P(4-FC
3
6 4
H )
a
b
c
d
A A E
Conversion CZ100!ee /(ee Cee ).
13
Selectivity factor reproducible to G1 in parallel runs.
ee Of recovered alcohol, established by CSP-HPLC.
ee Of ester, established by CSP-HPLC on derived alcohol following saponification.
will help unravel the complex interplay of factors
responsible for catalysis and chirality transfer in these
(w1 mg/5 mL) with a Jasco J600 spectropolarimeter using
10 mm quartz cuvettes at 20 8C.
1
8,19
reactions,
and reveal the role of the PPh additive.
3
0
0
00
0
thalen-1-yl)pyridin-4-yl]amine (2c). Method 1. To a
4
.1.1. (G)-Diethyl[3-(2-[1,1 ;3 ,1 ]terphenyl-5 -yl-naph-
4
. Experimental
2
1
suspension of 3-bromo-1,5-diphenylbenzene (420 mg,
1.36 mmol) and Mg (49 mg, 2.0 mmol) in THF (6 mL)
was added a crystal of I2 and the mixture sonicated
at 20–30 8C for 1 h. The resulting arylmagnesium
bromide was transferred via syringe to a solution of
1-(4-diethylaminopyridin-3-yl)naphthalen-2-yl trifluoro-
4
.1. General procedures
All reactions were performed under anhydrous conditions
and an atmosphere of nitrogen in oven-dried glassware.
Yields refer to chromatographically and spectroscopically
1
12
(
obtained from commercial sources or purified according to
H NMR) homogenous materials. Reagents were used as
methanesulfonate 1b (192 mg, 0.45 mmol) and PdCl2-
(dppp) (13 mg, 23 mmol) in THF (2 mL). The resulting
brown solution was stirred at rt for 30 min and refluxed for
21 h. After cooling to rt, the reaction mixture was quenched
with water (10 mL) and extracted with CH Cl . The
2
0
known procedures. Flash chromatography was carried out
using Merck Kiesegel 60 F254 (230–400 mesh) silica gel.
Only distilled solvents were used as eluents. Thin-layer
chromatography (TLC) was performed on Merck
2
2
combined extracts were dried (MgSO ), concentrated in
4
DC-Alufolien plates pre-coated with silica gel 60 F254,
which were visualised either by quenching of ultraviolet
vacuo and the residue purified by flash chromatography
(CH Cl /EtOAc) to give the recovered triflate 1b
1
2
2 2
fluorescence (lmaxZ254 nm) or by charring with 10%
(83 mg, 43%) and the title compound 2c (52 mg, 23%) as
a pale yellow oil. R Z0.60 (EtOAc); nmax/cm
K1
(CHCl3)
2976, 1586, 1498, 1265; dH (CDCl , 250 MHz) 0.49 (t,
KMnO in 0.1 M NaOH. All reaction solvents were distilled
immediately before use. Anhydrous CH Cl was obtained
4
f
2
2
3
by refluxing over CaH , toluene by refluxing over Na, and
2
JZ7.0 Hz, 6H), 2.57–2.91 (4H), 6.57 (d, JZ6.0 Hz, 1H),
7.30–7.69 (16H), 7.89–8.00 (3H), 8.31 (d, JZ6.0 Hz, 1H),
and 8.32 (s, 1H); d (CDCl , 63 MHz) 12.1 (2!CH ), 44.8
THF by refluxing over Na/benzophenone ketyl. Petrol refers
to the fraction of light petroleum boiling between 40–60 8C.
High-resolution mass spectrometry (HRMS) measurements
are valid to G5 ppm. CSP-HPLC was performed on a
Hewlett Packard Series 1100 instrument. CD spectra
C
3
3
(2!CH ), 112.1 (CH), 122.9 (C ), 124.2 (CH), 126.1 (CH),
q
2
126.6 (CH), 126.8 (CH), 127.2 (4!CH), 127.4 (2!CH),
127.5 (CH), 127.5 (CH), 128.2 (CH), 128.4 (CH), 128.8
(4!CH), 132.4 (C ), 133.3 (C ), 134.2 (C ), 138.4 (C ),
were recorded between 280 and 380 nm in CH CN
3
q
q
q
q

300
A. C. Spivey et al. / Tetrahedron 62 (2006) 295–301
1
41.0 (2!C ), 141.1 (2!C ), 142.5 (2!C ), 148.8 (CH),
q
by flash chromatography (hexane/EtOAc/hexane, 1:1) to
give boronic acid 3 (0.73 g, 81%) as a white powder. Mp
q
q
C
54.4 (CH), 155.0 (C ); m/z (EI ) (rel intensity) 504 (50%,
1
MH ), 503 (95%, M ), 488 (100), 231 (25), 57 (50);
q
C
C
K1
106.5–107.0 8C; R Z0.50 (EtOAc/hexane, 1:5); nmax/cm
f
C
HRMS calculated for C H N (MH ) 504.2565, found
(CHCl ) 2911, 1603, 1403, 1354, 1263, 844; d (CDCl3,
3
7
32
2
3
H
5
04.2555 (DZK2.0 ppm).
250 MHz) 2.38 (12H, s), 6.12 (2H, br s), 7.02 (2H, s), 7.30
4H, s), 7.94 (1H, t, JZ2.0 Hz), 8.05 (d, JZ2.0 Hz); dC
(CDCl , 63 MHz) 21.4 (4!CH ), 125.3 (4!CH), 129.1
(
Method 2. To a solution of 1-(4-diethylaminopyridin-
3
3
3
1
2
-yl)naphthalen-2-yl trifluoromethanesulfonate 1b
0.65 g, 1.5 mmol) in toluene (12 mL) was added K PO4
0.66 g, 3.0 mmol), LiCl (0.133 g, 3.0 mmol), Pd(OAc)2
0.035 g, 0.15 mmol), biphenyl-2-yl-dicyclohexylphos-
(3!CH), 132.4 (2!CH), 138.2 (4!C ), 141.2 (2!C ),
q q
C
(
(
(
141.6 (2!C ) [C -B not seen]; m/z (CI ) (rel intensity) 331
q q
3
C
C
(0.5%, MH ), 304 (50%), 286 [100%, MH KB(OH) ];
2
C
HRMS calculated for C H
2
{MH K[B(OH) ]}
2
2
22
phane (0.22 g, 0.6 mmol) and 3,5-diphenylbenzeneboronic
286.1722, found 286.1711 (DZK3.7 ppm).
2
2
acid (0.64 g, 2.3 mmol). The resulting orange solution was
stirred vigorously at 80 8C for 20 h and then at reflux for 4 h.
After cooling to rt, the reaction mixture was diluted with
satd Na CO (20 mL) and extracted with CH Cl2
(3!35 mL). The organic extracts were dried (MgSO4),
concentrated in vacuo and the residue purified by flash
0
terphenyl-5 -yl)naphthalen-1-yl]pyridin-4-yl}-amine
0
00
0
0
00
4.2.3. Diethyl{3-[2-(3,5,3 ,5 -tetramethyl[1,1 ;3 ,1 ]-
0
2
3
2
(2d). To a solution of 1-(4-diethylaminopyridin-3-yl)-
naphthalen-2-yl trifluoromethanesulfonate 1b (0.215 g,
1
2
0.5 mmol) in toluene (4 mL) was added K PO (0.215 g,
3
4
chromatography (CH Cl /EtOAc) to give terphenyl-
1.0 mmol), LiCl (0.043 g, 1.0 mmol), Pd(OAc) (0.011 g,
2
2
2
naphthylpyridine 2c (0.39 g, 50%) as a pale yellow oil.
Analytical data as above.
0.05 mmol), biscyclohexylbiphenylphosphine (0.071 g,
0.2 mmol) and boronic acid 3 (0.25 g, 0.75 mmol). The
resulting orange solution was stirred vigorously at 80 8C for
20 h and then at reflux for 4 h. After cooling to rt, the
reaction mixture was diluted with satd Na CO (20 mL) and
4.2. General procedure for the optical resolution
of (G)-2
2
3
extracted with CH Cl (3!35 mL). The organic extracts
2
2
The atropisomers were separated using semipreparative
CSP-HPLC by repeated injection of w2 mg of the racemate
in 15 mL of CH Cl . In all cases the levorotatory enantiomer
were dried (MgSO ), concentrated in vacuo and the residue
4
purified by flash chromatography (CH Cl /EtOAc) to
2
2
give the title compound 2d (0.110 g, 39%) as a pale yellow
oil. R Z0.65 (EtOAc); nmax/cm
2
2
K1
(
K)-2 eluted first. The enantiomers were further purified by
(CHCl ) 3008, 2931,
3
f
flash chromatography (EtOAc). Analytical CSP-HPLC
revealed O99.8% ee for both the levorotatory and the
dextrorotatory enantiomers. Assignment of the absolute
configuration of the atropisomeric axes follows from
correlation of the sign of the Cotton-effect peaks in their
CD spectra at w320 nm with that of biaryl (K)-2b for
which the absolute configuration has been unambiguously
established by X-ray crystallography [as its salt with N-Boc-
1589, 1502, 1379, 909, 850, 824; dH (CDCl , 250 MHz)
3
0.41 (6H, t, JZ7.0 Hz), 2.31 (12H, s), 2.56 (2H, dq, JZ7.0,
7.0 Hz), 2.73 (2H, dq, JZ7.0, 7.0 Hz), 6.55 (1H, d, JZ
6.0 Hz), 6.91 (2H, s), 6.98 (4H, s), 7.25 (2H, d, JZ1.0 Hz),
7.39–7.51 (3H), 7.63 (1H, d, JZ8.0 Hz), 7.80–7.92 (3H),
8.25 (1H, s), 8.30 (1H, d, JZ6.0 Hz); d (CDCl , 63 MHz)
C
3
12.0 (2!CH ), 21.4 (4!CH ), 44.7 (2!CH ), 112.1 (CH),
122.9 (C ), 124.3 (CH), 125.1 (4!CH), 126.0 (CH), 126.6
3
3
2
q
1
0,12
O-benzyl-(S)-tyrosine].
(CH), 126.6 (CH), 127.3 (2!CH), 128.1 (CH), 128.3 (CH),
1
28.5 (CH), 128.9 (2!CH), 132.4 (C ), 133.2 (C ), 134.0
q
q
0
0
00
4
.2.1. (K)-(S ) and (C)-(R )-Diethyl[3-(2-[1,1 ;3 ,1 ]-
a
(C
(C
q
), 138.2 (4!C
), 148.6 (CH), 154.3 (CH), 154.9 (C ); m/z (EI ) (rel
q
q
), 141.1 (2!C
q
), 141.2 (2!C ), 142.1
q
a
0
C
terphenyl-5 -yl-naphthalen-1-yl)pyridin-4-yl]amine
2c). CSP-HPLC conditions: Chiralcel OD (1 cm!25 cm);
hexanes/EtOAc/Et NH, 85:14.4:0.6; 3 mL min ; 35 8C;
q
C
C
(
intensity) 561 (MH , 50%), 560 (100%, M ), 545 (60),
531 (23); HRMS calculated for C41
K1
C
(M ) 560.3191,
H
N
2
2
40
UV detection at 250 nm, reference at 525 nm. (K)-(S )-2c,
a
found 560.3204 (DZC2.3 ppm).
white solid. Mp 80.5–82.0 8C, spectroscopic data as above;
retention time 20.3 min; [a] K113 (c 1.4 in CHCl ); CD
lmax/nm 320 (Kive). (C)-(R )-2c, white solid. Mp
a
2
D
5
00 00
4.2.4. (K)-(S ) and (C)-(R )-Diethyl{3-[2-(3,5,3 ,5 -
a a
tetramethyl[1,1 ;3 ,1 ]terphenyl-5 -yl)naphthalen-1-yl]-
pyridin-4-yl}amine (2d). CSP-HPLC conditions: Chiralcel
3
0
0
00
0
8
2
1.0–82.0 8C, spectroscopic data as above; retention time
6.9 min; [a] C112 (c 1.4 in CHCl ); CD lmax/nm 320
2
D
5
OD (1 cm!25 cm); hexanes/EtOAc/Et NH, 89:10.6:0.4;
2
3
K1
3 mL min ; 30 8C; UV detection at 254 nm, reference at
(
Cive).
3
60 nm. (K)-(S )-2d, colourless oil, spectroscopic data as
a
25
4
.2.2. 3,5-Bis(3,5-dimethylphenyl)benzeneboronic acid
3). To a solution of 1,5-bis(3,5-dimethylphenyl)-3-bromo-
above; retention time 13.1 min; [a]
D
K90 (c 1.6 in CHCl
)-2d, colourless oil,
spectroscopic data as above; retention time 21.4 min;
3
);
(
benzene (1.0 g, 2.7 mmol) in Et O (25 mL) was added
CD lmax/nm 320 (Kive). (C)-(R
a
1
2
2
2
5
n-BuLi (1.20 mL, 2.5 M, 3.0 mmol) in hexanes at K78 8C.
The reaction was stirred for 0.5 h at K78 8C, warmed to
[a] C89 (c 1.4 in CHCl ); CD lmax/nm 320 (Cive).
D 3
0 8C over 15 min and then stirred at this temperature for a
further 1.5 h. After re-cooling to K78 8C, the reaction
4.3. General procedure for catalytic acylative KR
(Table 1; except entry 5)
mixture was treated with B(OMe) (0.9 mL, 3.3 mmol) and
3
allowed to warm to rt over 1.5 h. The reaction mixture was
then treated with 1 M HCl (20 mL) and extracted with
CH Cl (3!30 mL). The organic extracts were dried
A solution of (G)-alcohol 4 (1.00 mmol), Et N (104 mL,
3
0.75 mmol) and catalyst (K)-(S )-2 (0.01 mmol, O99.8%
a
ee) in toluene (2 mL) was cooled to K78 8C. Ac O (83 mL,
0.75 mmol) was then added dropwise with vigorous stirring.
2
2
2
(
MgSO ), concentrated in vacuo and the residue purified
4

A. C. Spivey et al. / Tetrahedron 62 (2006) 295–301
301
After 6.0–11.3 h (see table) at K78 8C the reaction was
Acknowledgements
quenched by the dropwise addition of MeOH (3 mL), the
reaction mixture was allowed to warm to rt over 15 min, and
the solvents were evaporated in vacuo. The alcohol and its
ester were separated by flash chromatography (petrol/
CH Cl , 2:1/CH Cl ). The ester was hydrolysed by
Grateful acknowledgement is made to the BBSRC, the
EPSRC and the Leverhulme Trust for financial support of
this work. Merck Sharp & Dohme Ltd and Pfizer Ltd are
also thanked for unrestricted research funds.
2
2
2
2
heating at reflux in a solution of 5% NaOH/MeOH (2 mL)
for 5 min. After removal of the solvent the residue was
passed through a small plug of flash silica eluting with
EtOAc. The enantiomeric excesses for the unreacted alcohol
and alcohol obtained from hydrolysis of the ester were
established by CSP-HPLC.
References and notes
1
. France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev.
003, 103, 2985–3012.
2
4
(
(
.4. Optimal procedure for catalytic acylative KR of
G)-1-(1-naphthyl)ethanol 4c at rt using catalyst 2b
2
. Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481–2495.
. Spivey, A. C.; Maddaford, A.; Redgrave, A. Org. Prep.
Proced. Int. 2000, 32, 331–365.
3
Table 3, entry 11)
4
. Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
. Fu, G. C. Acc. Chem. Res. 2004, 37, 542–547 and references
therein.
To a solution of (G)-alcohol 4c (600 mg, 3.48 mmol), 2,6-
di-t-butylpyridine (391 mL, 1.74 mmol), triphenylphosphine
5
(
915 mg, 3.48 mmol) and catalyst (K)-(S )-2b (12.3 mg,
a
6
7
8
9
. Miller, S. J. Acc. Chem. Res. 2004, 37, 601–610 and references
therein.
. Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 2003, 125,
3
.5 mmol, O99.8% ee) in t-amyl alcohol (7 mL) was added
(
i-PrCO) O (263 mL, 1.74 mmol) dropwise with vigorous
2
stirring. After 1 h the solvent was evaporated in vacuo and
the residue purified by flash chromatography (petrol/
CH Cl , 2:1/CH Cl ) to give alcohol 4c as a colourless
4
166–4173 and references therein.
. Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kibane, C. J.
J. Am. Chem. Soc. 2004, 126, 12226.
2
2
2
2
oil (280 mg, 47, 81.4% ee by CSP-HPLC) and its ester 5c as
a colourless oil (438 mg, 52, 72.4% ee as determined
following hydrolysis then CSP-HPLC, as above).
. Terakado, D.; Koutaka, H.; Oriyama, T. Tetrahedron:
Asymmetry 2005, 16, 1157–1165 and references therein.
1
1
1
1
1
1
0. Spivey, A. C.; Leese, D. P.; Zhu, F.; Davey, S. G.; Jarvest,
R. L. Tetrahedron 2004, 60, 4513–4525.
4
.5. CSP-HPLC analysis of chiral alcohols (Tables 1–3).
1. Spivey, A. C.; Zhu, F.; Mitchell, M. B.; Davey, S. G.; Jarvest,
R. L. J. Org. Chem. 2003, 68, 7379–7385.
2. Spivey, A. C.; Fekner, T.; Spey, S. E. J. Org. Chem. 2000, 65,
4
.5.1. 1-Phenylethanol 4a. Chiralcel OD (0.46 cm!
5 cm); hexanes/i-PrOH, 99:1; 1 mL min ; 0 8C; UV
K1
2
detection at 211 nm, reference at 525 nm. Retention times:
31 min (R), 49 min (S). Assigned by comparison with
authentic samples supplied by Aldrich.
3
154–3159.
3. Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18,
49–330.
4. Fu, G. C.; Ruble, J. C.; Tweddell, J. J. Org. Chem. 1998, 63,
794–2795.
2
3
2
2
4
.5.2. 1-Phenylpropanol 4b. Chiralcel OD (0.46 cm!
K1
5 cm); hexanes/i-PrOH, 97:3; 1 mL min ; 25 8C; UV
5. Schwessinger, R.; Hasenfratz, C.; Schlemper, H.; Walz, L.;
Peters, E.-M.; Peters, K.; von Schnering, H. G. Angew. Chem.,
Int. Ed. 1993, 32, 1361–1363.
2
detection at 211 nm, reference at 525 nm. Retention times:
2
4
1
5 min (S), 17 min (R).
1
6. Vogl, E. M.; Gr o¨ ger, H.; Shibasaki, M. Angew. Chem., Int. Ed.
1999, 38, 1570–1577.
4
.5.3. 1-(1-Naphthyl)ethanol 4c. Chiralcel OD (0.46 cm!
5 cm); hexanes/i-PrOH, 90:10; 1 mL min ; 25 8C; UV
K1
2
detection at 211 nm, reference at 525 vnm. Retention times:
1
17. Zhao, H.; Pandri, A.; Greenwald, R. B. J. Org. Chem. 1998,
63, 7559–7562.
18. Spivey, A. C.; Arseniyadis, S. Angew. Chem., Int. Ed. 2004,
2
3
2 min (S), 24 min (R).
4
3, 5436–5441.
4.5.4. 1-(2-Tolyl)ethanol 4d. Chiralcel OD (1 cm!25 cm);
hexanes/i-PrOH, 99:1; 3 mL min ; 30 8C; UV detection at
19. Xu, S.; Held, I.; Kempf, B.; Mayr, H.; Steglich, W.; Zipse, H.
Chem. Eur. J. 2005, 11, 4751–4757.
K1
2
2
20 nm, reference at 360 nm. Retention times: 6.1 min (S),
6.4 min (R).
20. Armarego, W. C. F.; Chai, C. L. L. Purification of Laboratory
Chemicals, 5th ed.; Pergamon: Oxford, 2003.
2
5
2
1. Du, C.-J.F.; Hart, H.; Ng, K.-K.D. J. Org. Chem. 1986, 51,
3162–3165.
4
.5.5. 1-(2-Methoxyphenyl)ethanol 4e. Chiralcel OD
K1
(
0.46 cm!25 cm); hexanes/i-PrOH, 90:10; 1 mL min ;
5 8C; UV detection at 211 nm, reference at 525 nm.
22. Miller, T. M.; Neenan, T. X.; Zayas, R.; Bair, H. E. J. Am.
Chem. Soc. 1992, 114, 1018–1025.
23. Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 1999, 121,
2
Retention times: 12 min (S), 19 min (R).
2
3
5
813–5814.
4
.5.6. 1-(2,6-Dimethylphenyl)ethanol 4f. Chiralcel OD
1 cm!25 cm); hexanes/i-PrOH, 93:7; 3 mL min ; 30 8C;
24. Naemura, K.; Murata, M.; Tanaka, R.; Yano, M.; Hirose, K.;
Tobe, Y. Tetrahedron: Asymmetry 1996, 7, 3285–3294.
25. Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1995, 117, 7562–7563.
K1
(
UV detection at 210 nm, reference at 360 nm. Retention
times: 8.6 min (R), 10.3 min (S).
2
3