Asymmetric synthesis of diarylmethanols: Development of a hemilabile phosphorus ligand based on the concept of conformational control

Article abstract of DOI:10.1055/s-2006-950315

The asymmetric synthesis of diarylmethanols using a new hemilabile phosphorus ligand based on the concept of conformational control is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950315

PAPER
3809
Asymmetric Synthesis of Diarylmethanols: Development of a Hemilabile
Phosphorus Ligand Based on the Concept of Conformational Control
A
T
symmetric Sy
a
nthesis of
D
k
iarylmethan
ao ls fumi Arao, Kiyoto Suzuki, Kazuhiro Kondo,* Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Fax +81(52)8363439; E-mail: kazuk@phar.nagoya-cu.ac.jp; E-mail: aoyama@phar.nagoya-cu.ac.jp
Received 2 June 2006; revised 14 July 2006
commercially available or are straightforward to prepare,
to the preparation of chiral diarylmethanols.
Abstract: The asymmetric synthesis of diarylmethanols using a
new hemilabile phosphorus ligand based on the concept of confor-
mational control is described.
4g
4a
Miyaura has reported rhodium–2-(diphenylphosphino)-
5
Keywords: chiral ligand, asymmetric synthesis, diarylmethanol, 2¢-methoxy-1,1¢-binaphthyl (Rh–MOP) catalyzed asym-
rhodium catalyst, boronic acid
metric phenylation of 1-naphthaldehyde (3a) with phenyl-
boronic acid giving 1-naphthyl(phenyl)methanol (4a)
with 41% ee. We first chose 2 as a substrate and began to
screen a variety of 4,5-bis[(diarylphosphino)methyl]-1,3-
dioxolane derivatives 2 as the precursor of hemilabile
We have been interested in developing novel chiral
1
ligands based on the concept of conformational control.
6
phosphorus ligand 1. Since hemilabile phosphorus ligand
In order to expand the scope of our concept, we planned
2
1
was found to be very easily oxidized to bis-phosphine
to develop novel hemilabile phosphorus ligand 1 with
oxide 5 in air, it was initially decided to produce 1 in situ
with a rhodium(III) complex. The results are shown in
Table 1. Reactions were carried out with 2.0 equivalents
of sodium tert-butoxide as a base and phenylboronic acid
in 1,2-dimethoxyethane–water (5:1) at 100 °C. First, the
both soft and hard coordinated centers within one mole-
cule. Figure 1 shows the possible design of a novel hemi-
labile ligand 1, such that the soft diarylphosphino group
(
PAr ) coordinates with a soft metal and the hard di-
2
arylphosphoryl group (POAr ) coordinates with a hard
2
effects of the pendant diarylphosphino (PAr ) group were
metal. These two types of coordination allow conforma-
tional fix of a soft metal–hard metal–hemilabile ligand 1
complex, leading to the creation of a favorable reaction
environment.
2
examined. As shown in Table 1, entries 1 and 2, the pen-
dant diarylphosphino group plays an important role: com-
pare Ar = Ph (58% yield, 2% ee) and Ar = 4-MeO-3,5-
7
2
Me C H (97% yield, 75% ee). In the case of entry 2,
2
6
only a fragment of the monophosphine oxide sodium salt
6 was observed in the reaction mixture by ESI-MS
Ar2
O
O
P
soft metal
R
R
PAr2
O
[HRMS: calcd for C H NaO P : 769.3393; found:
43 56 7 2
1
hard metal
769.3433]. As shown in Figure 2, a linear correlation be-
tween the enantiomeric excess of the ligand and that of the
product 4a was observed, indicating that a 1:1 ratio of
ligand to rhodium is present in the catalytic complex. Fur-
thermore, under the reaction conditions (Table 1, entry 3)
Figure 1 Possible design of a soft metal–hard metal–hemilabile li-
gand 1 complex
There are two typical approaches to the catalytic asym- where the hemilabile phosphorus ligand 1 was not pro-
metric synthesis of diarylmethanols, reduction of the cor- duced, 4a was produced with low enantioselectivity. The
3
responding diaryl ketones or arylation of aromatic results for the effect of other pendant diarylphosphino
4
aldehydes. However, efficient methods for the catalytic groups were as follows: R = Me, Ar = 4-i-PrO-3,5-
asymmetric synthesis of optically active diarylmethanols Me C H (67% yield, 32% ee), R = Me, Ar = 4-MeO-3,5-
2
6
2
are limited. We were interested in applying the novel i-Pr C H (65% yield, 40% ee). Next, the effect of the
2
6
2
hemilabile ligand 1 to the rhodium-catalyzed asymmetric acetal moiety was examined (Table 1, entries 4–6), and it
phenylation of aromatic aldehydes with phenylboronic was shown that the acetal moiety also plays an important
acids as follows: (1) No successful examples for this rhod- role (Ar = 4-MeO-3,5-Me C H ): R = H, 2c (62% yield,
2
6
2
ium-catalyzed asymmetric phenylation of aromatic alde- 8% ee); R = i-Pr, 2d (79% yield, 32% ee); R = Ph, 2e
4
a–d
hydes have been reported.
methods4e for the arylation of aromatic aldehydes make possessing Ar = 4-MeO-3,5-Me C H
2
(2) Some successful (86% yield, 55% ee). With the best ligand precursor 2b
[(R,R)-MOD-
2
6
use of air-sensitive organozinc reagents, which limit DIOP], the use of other bases such as potassium hydrox-
large-scale application. A solution could be the applica- ide (90% yield, 17% ee), lithium hydroxide (97% yield,
tion of arylboronic acids, which are easy to handle and are 17% ee), rubidium hydroxide (92% yield, 23% ee), cesi-
um hydroxide (90% yield, 33% ee), and sodium methox-
SYNTHESIS 2006, No. 22, pp 3809–3814
x
x
.x
x
.
2
0
0
6
ide (95% yield, 43% ee) led to disappointing results.
Other solvents such as dioxane–water, toluene–water,
N,N-dimethylformamide–water, and propan-1-ol, and
Advanced online publication: 12.10.2006
DOI: 10.1055/s-2006-950315; Art ID: F09006SS
Georg Thieme Verlag Stuttgart · New York
©

3810
T. Arao et al.
PAPER
Table 1 Ligand Screeninga
O
R
PAr2
PAr2
R
O
2
(3 mol%)
O
O
O
PAr2
O
O
PAr2
Na+
R
R
RhCl3⋅3H2O (3 mol%)
NaOt-Bu (2.0 mol equiv)
DME–H2O (5:1), 100 °C
PAr2
O
PAr2
O
5
6
: Ar =
OMe
O
O
PAr2
PAr2
R
R
HO
Ph
CHO
*
O
1
PhB(OH)2 (2.0 mol equiv)
3a
4a
Entry
Ligand 2
Product 4a
b
c
Ar
Ph
R
Yield (%)
ee (%)
1
2a
2b
2b
2c
2d
2e
Me
Me
Me
H
58d
97
2 (R)
75 (R)
10
2
4-MeO-3,5-Me C H
2 6
2
3e
4
89
4-MeO-3,5-Me C H
62d
79d
86
8 (S)
2
6
2
2
2
5
4-MeO-3,5-Me C H
i-Pr
32 (R)
55 (R)
2
6
6
4-MeO-3,5-Me C H
Ph
2
6
a
Reaction conditions; for details, see experimental section.
Isolated yield.
Determined by HPLC analysis (Daicel chiralcel OD-H).
Remainder of mass balance was the starting aldehyde 3a.
b
c
d
e
[
RhCl(coe) ] was used. These reaction conditions do not produce hemilabile phosphorus ligand 1.
2 2
other ratios of 1,2-dimethoxyethane–water gave less sat- Enantiomerically pure 4c (>99% ee), which was obtained
isfactory results. Unfortunately, the reaction with 4-meth- by simple recrystallization from ethyl acetate–hexane,
8
oxy- and 4-chlorophenylboronic acids did not proceed: was transformed into an antihistaminic (R)-neobenodine
the reason is not clear at the present time.
(7) as shown in Scheme 1.
9
Having established the best conditions, we examined the We were next interested in applying borane complex 8,
reaction of several aromatic aldehydes 3. The results are which is considered to be air-stable, to the above phenyla-
shown in Table 2. Various substituted aromatic aldehydes tion. Borane complex 8 was synthesized as shown in
could be employed, giving the corresponding products 4 Scheme 2, and it was employed in the phenylation of 1-
with good enantioselectivity (up to 85% ee). The results naphthaldehyde (3a) (Scheme 3). Borane complex 8 can
are, to the best of our knowledge, the best enantioselectiv- be utilized in this phenylation, although, compared with
ity in the reported literature for the rhodium-catalyzed the result of Table 1 (entry 2) the use of 8 decreased the
phenylation of aromatic aldehydes. Unfortunately, the re- enantioselectivity in the formation of 4a somewhat.
action with 4-methoxy- and 4-chlorophenylboronic acids
did not proceed: the reason is not clear at the present time.
We propose that the rhodium(I)–1b complex is the key in-
termediate in the catalytic cycle of the phenylation that is
responsible for discriminating between the enantiotopic
1
0
faces of the aldehyde. Plausible reaction mechanisms
are considered as follows. The transmetalation between
phenylboronic acid and the rhodium(I)–1b complex as
shown in Figure 3 occurs. The aldehyde coordinates enan-
tiodiscriminatively to the PhRh(I)–1b complex
(
Figure 4), and then the formyl group inserts into the
formed Ph–Rh bond. In this insertion, enantiodiscrimina-
tion of the aldehyde as shown in Figure 4 might be kept,
although further detailed investigation is needed, and so
the phenylation with the rhodium(I)–1b complex would
give good enantioselectivity.
Figure 2
Synthesis 2006, No. 22, 3809–3814 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Diarylmethanols
3811
Table 2 Substrate Generalitya
Ar2
Ar2
Rh
P
X
2b
O
RhCl3⋅3H2O (3 mol%)
O
–
Na+
NaOt-Bu (2.0 mol equiv)
B
(
OH)3
DME–H2O (5:1), 100 °C
P
O
2
Ar2 Ar
2
Figure 3 Plausible transition state in transmetalation.
O
O
P(Ar )2
2
P(Ar )2
O
1b
OH
1
Ar2 Ar2
P Rh
H
Ar1
Ar -CHO
Ar2
Ar2
P Rh
Ar1
PhB(OH)2 (2.0 mol equiv)
Ph
3
Ar1
O
4
O
H
O
O
>
Ar1
O
O
Entry
3,4
Product 4
Yield (%)
eeb,c (%)
67 (R)
P
O
P
O
Ar
Ar2 Ar
2
Ar2
2
1
2
3
4
5
6
b
c
d
e
f
2-naphthyl
4-MeC H
94
91
91
90
97
94
90
Figure 4 Favorable coordination of the aldehyde to the PhRh–1b
79 (R)
complex.
6
4
4-i-PrC H
75 (n.d.)
85 (R)
6
4
In summary, we have developed a new hemilabile phos-
phorus ligand based on the concept of conformational
control. Development of other hemilabile phosphorus
4-MeOC H
6
4
4
4-FC H
76 (R)
6
4
1
1
ligands is now in progress.
g
h
3-MeC H
71 (n.d.)
70 (n.d.)
6
4
7
3-MeOC H
IR spectra were measured on a SHIMADZU FTIR-8100 diffraction
grating IR spectrophotometer. H and C NMR spectra were mea-
6
1
13
a
The reactions were performed using: aromatic aldehydes 3,
1
sured on a JEOL JNM-EX-270 NMR spectrometer, H NMR (270
2
RhCl ·3H O (3 mol%), (R,R)-MOD-DIOP (2b; Ar = 4-MeO-3,5-
3
2
13
MHz) and C NMR (68 MHz ) with TMS as an internal reference.
Me C H ), PhB(OH) (2 mol equiv), NaOt-Bu, DME–H O (5:1),
2
6
2
2
2
EI and FAB MS spectra were measured on a JEOL JMS-SX-102A
instrument. Specific rotations (in deg cm g L ) were determined
on a JASCO DIP-1000 digital polarimeter.
1
00 °C, 72 h.
3
–1 –1
b
Determined by HPLC; for details, see experimental section.
c
n.d. = not determined.
RhCl ·3H O, DIOP 2a, (R,R)-MOD-DIOP 2b, aromatic aldehydes,
3
2
arylboronic acids, and other reagents were available from commer-
cial sources and used without further purification. In general, all re-
actions were performed under an argon atmosphere. DME, 1,4-
dioxane, THF, and toluene were distilled from Na/benzophenone
NMe2
O
OH
Ph
1)
O
Cl
NaH, THF
) LiAlH4, THF, reflux
NMe2
Ph
ketyl under N . Other solvents were available from commercial
2
2
sources and used without further purification. Silica gel column
chromatography was performed on Fuji silysia PSQ 60B.
4
c
7
84% (2 steps)
>
99% ee
>99% ee
The diol and ditosylate as shown below were prepared according to
reported procedures.
1
2
Scheme 1 Conversion of 4c to antihistaminic (R)-neobenodine 7.
(
4R,5R)-4,5-Bis(hydroxymethyl)-1,3-dioxolane
O
O
PAr2
PAr2
BH3
26
1
) BH3⋅THF (1 mol equiv)
Brown oil; [a]D –10 (c 1.14, THF).
IR (neat): 3397 cm–1.
THF, –78 °C
O
O
PAr2
PAr2
O
2
) 1% H2O2, EtOAc, 0 °C
1
H NMR (CDCl ): d = 3.66–3.88 (m, 2 H × 2), 3.90–3.98 (m, 1 H ×
3
8
2
b: Ar =
OMe
44% (2 steps)
2), 5.04 (br s, 2 H).
13
C NMR (CDCl ): d = 61.68 (br), 62.13, 77.99, 94.48 (br), 95.06.
3
+
Scheme 2 Synthesis of borane complex 8.
MS (FAB): m/z = 135 (M + 1).
Anal. Calcd for C H O : C, 44.77; H, 7.51. Found: C, 44.29; H,
5
10
4
7
.92.
HO
Ph
CHO
RhCl3⋅3H2O (3 mol%)
Ligand 8 (3 mol%)
(4R,5R)-4,5-Bis(hydroxymethyl)-2,2-diisopropyl-1,3-dioxolane
Colorless viscous oil; [a]D +9 (c 1.81, THF).
2
1
PhB(OH)2 (2.0 mol equiv)
NaOt-Bu (2.0 mol equiv)
DME–H2O (5:1)
–
1
3a
4a
IR (neat): 3380 cm .
8
2%, 63% ee
1
100 °C, 48 h
H NMR (CDCl ): d = 0.94 (d, J = 6.8 Hz, 3 H × 4), 2.09 (sept,
3
J = 6.8 Hz, 1 H × 2), 2.27–2.42 (br, 1 H × 2), 3.68–3.88 (br, 2 H ×
2), 3.90–4.00 (br, 1 H × 2).
Scheme 3 Standard asymmetric phenylation with borane complex
8
.
13
C NMR (CDCl ): d = 17.47, 17.57, 34.24, 62.71, 80.79, 116.20.
3
Synthesis 2006, No. 22, 3809–3814 © Thieme Stuttgart · New York

3812
T. Arao et al.
PAPER
+
MS (EI): m/z = 187 (M – CH OH, base peak), 175, 71.
added NaH (60% in mineral oil, 80.8 mg, 2.02 mmol) at 0 °C. The
mixture was stirred at 40 °C for 1 h, allowed to cool, diluted with
2
+
HRMS: m/z [M – CH OH] calcd for C H O S : 187.1334; found:
2
47 64
6 2
H O, and extracted with EtOAc. The combined extracts were
2
187.1321.
washed with brine, dried (Na SO ), and concentrated. The residue
2
4
+
MS (FAB): m/z = 219 (M + 1).
was dissolved in Et NH (10 mL). The whole mixture was stirred at
2
5
0 °C for 5 h and concentrated. Purification by column chromatog-
(
4R,5R)-4,5-Bis(hydroxymethyl)-2,2-diphenyl-1,3-dioxolane
raphy (silica gel, EtOAc–hexane, 1:19 to 1:4) gave 2e as a white
amorphous solid; yield: 418 mg (97%, 2 steps); [a]D –29 (c 1.07,
THF).
2
5
White solid; mp 91–93 °C; [a]D +33 (c 1.09, THF).
25
–
1
IR (Nujol): 3285 cm .
–1
1
IR (Nujol): 1217, 1016 cm .
H NMR (CDCl ): d = 1.84 (dd, J = 7.6, 4.9 Hz, 1 H × 2), 3.62–3.88
3
(
(
1
m, 2 H × 2), 4.19–4.28 (m, 1 H × 2), 7.21–7.39 (m, 6 H), 7.43–7.55
1
H NMR (CDCl ): d = 2.10–2.42 (m, 2 H × 2), 2.22 (s, 3 H × 4),
3
m, 4 H).
2
.25 (s, 3 H × 4), 3.69 (s, 3 H × 2), 3.71 (s, 3 H × 2), 3.96 (br t,
3
J = 6.9 Hz, 1 H × 2), 7.06 (d, J = 7.8 Hz, 2 H × 2), 7.12 (d, J = 7.8
Hz, 2 H × 2), 7.15–7.23 (m, 6 H), 7.24–7.32 (m, 4 H).
C NMR (CDCl ): d = 62.17, 79.25 (br), 125.89 (br), 128.23 (br),
3
1
42.58.
13
+
C NMR (CDCl ): d = 16.23 (br), 32.14, 32.34, 59.62, 59.64,
MS (FAB): m/z = 287 (M + 1).
3
8
1
1
1.01, 81.13, 81.25, 81.37, 108.73, 125.68, 127.43 (br), 127.73,
30.60, 130.71, 130.74, 130.86, 133.00 (br), 133.30, 133.33,
Anal. Calcd for C H O : C, 71.31; H, 6.34. Found: C, 71.25; H,
6
17
18
4
.31.
33.64, 143.71, 157.43, 157.52.
+
MS (EI): m/z = 553 (M – PAr ), 301 (base peak).
(
4R,5R)-4,5-Bis(tosyloxymethyl)-1,3-dioxolane
2
2
6
Yellow amorphous solid; [a]D –37 (c 1.20, THF).
+
HRMS: m/z [M – PAr ] calcd for C H O P: 553.2508; Found:
2
35 38
4
–
1
553.2525.
IR (Nujol): 1360, 1177 cm .
+
1
MS (FAB): m/z = 856 (M + 2).
H NMR (CDCl ): d = 2.46 (s, 3 H × 2), 3.98–4.16 (m, 6 H), 4.89
s, 2 H), 7.36 (d, J = 8.2 Hz, 2 H × 2), 7.78 (d, J = 8.2 Hz, 2 H × 2).
3
(
(
4R,5R)-4,5-Bis{[bis(4-methoxy-3,5-dimethylphenyl)phosphi-
no]methyl}-1,3-dioxolane (2c)
The typical procedure afforded the title compound in 83% yield (2
steps) as a white amorphous solid; [a]D –1.2 (c 2.03, THF).
13
C NMR (CDCl ): d = 21.76, 68.10 (br), 74.83, 95.76, 127.86,
3
1
29.91, 132.22, 145.20.
+
25
MS (EI): m/z = 442 (M ), 155, 91 (base peak).
+
IR (Nujol): 1217, 1016 cm–1.
HRMS: m/z [M ] calcd for C H O S : 442.0756; found: 442.0741.
1
9
22
8 2
1
H NMR (CDCl ): d = 2.20–2.35 (m, 2 H × 2), 2.24 (s, 3 H × 4),
3
(
4R,5R)-2,2-Diisopropyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane
2
.25 (s, 3 H × 4), 3.71 (br s, 3 H × 4), 3.82 (dd, J = 10.1, 5.4 Hz, 1
2
5
Colorless powder; mp 90 °C (hexane–EtOAc); [a] –18 (c 1.06,
THF).
D
H × 2), 4.96 (br s, 2 H), 7.07 (d, J = 8.2 Hz, 2 H × 2), 7.10 (d, J = 8.2
Hz, 2 H × 2).
–
1
IR (Nujol): 1364, 1177 cm .
13
C NMR (CDCl ): d = 16.20 (br), 16.26 (br), 32.53, 32.57, 32.74,
3
1
H NMR (CDCl ): d = 0.78 (d, J = 6.8 Hz, 3 H × 2), 0.79 (d, J = 6.8
32.79, 59.55 (br), 79.63, 79.74, 79.86, 79.97, 94.04 (br), 130.73,
130.78, 130.84, 130.90, 130.99, 132.81, 133.06, 133.10, 133.37,
157.38, 157.48, 157.56 (br).
3
Hz, 3 H × 2), 1.97 (sept, J = 6.8 Hz, 1 H × 2), 2.46 (s, 3 H × 2), 3.86–
3
×
.98 (m, 1 H × 2), 4.02–4.18 (m, 2 H × 2), 7.36 (d, J = 8.1 Hz, 2 H
2), 7.78 (d, J = 8.1 Hz, 2 H × 2).
+
MS (EI): m/z = 702 (M ), 401 (base peak).
13
C NMR (CDCl ): d = 17.15, 17.33, 21.73, 34.01, 68.38, 76.38,
+
3
HRMS: m/z [M ] calcd for C H O P : 702.3239; found: 702.3255.
4
1
52
6 2
1
17.76, 127.90 (br), 129.85, 132.28 (br), 145.04.
+
MS (FAB): m/z = 527 (M + 1).
(4R,5R)-4,5-Bis{[bis(4-methoxy-3,5-dimethylphenyl)phosphi-
no]methyl}-2,2-diisopropyl-1,3-dioxolane (2d)
Anal. Calcd for C H O S : C, 57.01; H, 6.51. Found: C, 57.34; H,
25
34
8 2
The typical procedure afforded the title compound in 84% yield (2
6.75.
2
4
steps) as a white amorphous solid; [a]D –1.8 (c 1.12, THF).
–
1
(
4R,5R)-2,2-Diphenyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane
IR (Nujol): 1218, 1018 cm .
2
5
Colorless powder; mp 118–119 °C (hexane–EtOAc); [a] –12 (c
1
1
D
H NMR (CDCl ): d = 0.77 (d, J = 6.6 Hz, 3 H × 2), 0.85 (d, J = 6.6
3
.12, THF).
Hz, 3 H × 2), 1.95 (sept, J = 6.6 Hz, 1 H × 2), 2.25–2.34 (m, 2 H ×
2), 2.28 (s, 3 H × 8), 3.67–3.87 (br, 1 H × 2), 3.74 (s, 3 H × 4), 7.14
(d, J = 7.1 Hz, 2 H × 2), 7.17 (d, J = 7.1 Hz, 2 H × 2).
–
1
IR (Nujol): 1370, 1191 cm .
1
H NMR (CDCl ): d = 2.45 (s, 3 H × 2), 3.92–4.04 (m, 1 H × 2),
3
13
4
.05–4.15 (m, 2 H × 2), 7.21–7.37 (m, 10 H), 7.32 (d, J = 8.4 Hz, 2
C NMR (CDCl ): d = 16.10, 17.35 (br), 17.46 (br), 31.15–32.04
3
(m), 33.97 (br), 59.51 (br), 80.70–81.06 (m), 115.66 (br), 130.30–
H × 2), 7.73 (d, J = 8.4 Hz, 2 H × 2).
1
3
131.00 (m), 133.07 (d, J = 19.7 Hz), 133.24 (d, J = 19.6 Hz), 157.51
C NMR (CDCl ): d = 21.77, 68.43, 76.13 (br), 110.94, 125.88,
3
(
br).
1
27.88, 128.04, 128.33 (br), 129.87, 132.24, 141.43, 145.05.
+
+
MS (EI): m/z = 786 (M ), 301 (base peak).
MS (FAB): m/z = 595 (M + 1).
+
HRMS: m/z [M ] calcd for C H O P : 786.4178; found: 786.4205.
4
7
64
6 2
Anal. Calcd for C H O S : C, 62.61; H, 5.08. Found: C, 62.35; H,
31
30
8 2
5.14.
(R)-1-Naphthyl(phenyl)methanol (4a); Typical Procedure
To a stirred soln of RhCl ·3 H O (3.95 mg, 0.0150 mmol) in DME–
3
2
(
4R,5R)-4,5-Bis{[bis(4-methoxy-3,5-dimethylphenyl)phosphi-
H O (5:1, 2.4 mL) were added (R,R)-MOD-DIOP (2b, 11.0 mg,
2
no]methyl}-2,2-diphenyl-1,3-dioxolane (2e); Typical Procedure
To a stirred soln of (4R,5R)-2,2-diphenyl-4,5-bis(tosyloxymethyl)-
1
0
.0150 mmol), t-BuONa (96.1 mg, 1.00 mmol), PhB(OH) (122
2
mg, 1.00 mmol), and 1-naphthaldehyde (3a, 78.1 mg, 0.500 mmol)
at r.t. The mixture was stirred at 100 °C for 72 h under argon, al-
,3-dioxolane (300 mg, 0.504 mmol) and (4-MeO-3,5-
Me C H ) PH·BH (479 mg, 1.51 mmol) in DMF (3.0 mL) was
2
6
2 2
3
Synthesis 2006, No. 22, 3809–3814 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Diarylmethanols
3813
lowed to cool, diluted with H O, and extracted with EtOAc. The
THF (6.0 mL). LiAlH (127 mg, 3.34 mmol) was added to the
2
4
combined extracts were washed with brine, dried (Na SO ), and
stirred to soln at 0 °C. The mixture was refluxed for 3 h and allowed
to cool. Na SO ·10H O was gradually added to the mixture. The
whole mixture was stirred at r.t. for 6 h, filtered to remove the white
precipitates, and concentrated. The residue was purified by column
2
4
concentrated. The residue was purified by column chromatography
silica gel, EtOAc–hexane 1:19 to 1:9) to give 4a as a colorless oil;
yield: 114 mg (97%); 75% ee (Daicel chiralcel OD-H, hexane–i-
2
4
2
(
4a
PrOH). The spectral data of 4a were comparable to those reported.
chromatography (silica gel, MeOH–CHCl , 1:19 to 1:9) to give (R)-
3
neobenodine (7); yield: 405 mg (84%, 2 steps). The spectral data
2
D
0
(
1
R)-2-Naphthyl(phenyl)methanol (4b)
3 The ee was determined by HPLC analysis (Daicel chiralcel OD-
were comparable to commercially available racemate; [a] +12 (c
0.807, THF).
H, hexane–i-PrOH). The absolute configuration was determined by
1
3
comparison with the reported specific rotation.
(4R,5R)-4-{[Bis(4-methoxy-3,5-dimethylphenyl)phosphino]me-
thyl}-5-{[bis(4-methoxy-3,5-dimethylphenyl)phosphoryl]meth-
yl}-2,2-dimethyl-1,3-dioxolane–Borane Complex (8)
(
R)-Phenyl(4-tolyl)methanol (4c)
14
The spectral data were comparable to those reported. The ee was
determined by HPLC analysis (Daicel chiralcel OD-H, hexane–i-
PrOH). The absolute configuration was determined by comparison
To a stirred soln of (–)-MOD-DIOP 2b (151 mg, 0.206 mmol) in
THF (2.06 mL) was added 1.0 M BH ·THF in THF (0.206 mL,
3
0.206 mmol) at –78 °C. The mixture was stirred at –78 °C for 1 h
3
b
with the reported specific rotation.
and diluted with H O. The mixture was warmed up to r.t. and ex-
2
tracted with EtOAc. The organic extracts were washed with brine,
dried (Na SO ), and concentrated. The crude product was used for
(+)-(4-Isopropylphenyl)(phenyl)methanol (4d)
2
4
The spectral data were comparable to a racemic authentic sample;
the next step without further separation. To a stirred soln of the
crude product in EtOAc (2.0 mL) was added 1% H O (1.0 mL) at
2
3
[
a]D +5.5 (c 0.490, benzene). The ee was determined by HPLC
2
2
analysis (Daicel chiralcel OD-H, hexane–i-PrOH).
0 °C. After stirring at 0 °C for 30 min, aq Na S O was added to the
2
2
3
mixture at 0 °C. The whole mixture was stirred at 0 °C for 10 min,
warmed to r.t., and extracted with EtOAc. The organic extracts were
washed with brine, dried (Na SO ), and concentrated. Purification
(
R)-(4-Methoxylphenyl)(phenyl)methanol (4e)
14
The spectral data were comparable to those reported. The ee was
determined by HPLC analysis (Daicel chiralcel OB-H, hexane–i-
PrOH). The absolute configuration was determined by comparison
2
4
by column chromatography (silica gel, EtOAc–hexane, 4:1) gave
BH complex 8 as a colorless amorphous solid; yield: 69.3 mg
3
3
b
27
with the reported specific rotation.
(44%, 2 steps); [a]D –3.9 (c 1.75, THF).
–
1
IR (Nujol): 1117 cm .
(
R)-(4-Fluorophenyl)(phenyl)methanol (4f)
1
15
H NMR (CDCl ): d = 1.19 (s, 3 H), 1.20 (s, 3 H), 1.96–2.66 (m, 4
The spectral data were comparable to those reported. The ee was
determined by HPLC analysis (Daicel chiralcel OB-H, hexane–i-
PrOH). The absolute configuration was determined by comparison
3
H), 2.26 (s, 12 H), 2.27 (s, 12 H), 3.71 (br s, 12 H), 4.00–4.16 (m, 2
H), 7.18–7.48 (m, 8 H).
1
6
with the reported specific rotation.
13
C NMR (CDCl ): d = 16.13, 16.16, 26.80, 26.94, 28.95, 29.50,
3
3
1
1
3.11, 34.15, 59.43–59.58 (br), 108.93, 123.15, 123.99, 124.85,
26.72, 127.27, 128.23, 128.78, 130.78, 130.84, 130.95, 130.98,
31.03, 131.13, 131.30, 131.31, 131.46, 131.51, 131.54, 131.69,
(
+)-Phenyl(3-tolyl)methanol (4g)
The spectral data were comparable to the commercially available
racemate. [a]D +3 (c 2.4, THF). The ee was determined by HPLC
analysis (Daicel chiralcel OB-H, hexane–i-PrOH).
2
0
132.38, 132.53, 132.93, 133.09, 159.07, 159.11, 159.18, 159.22,
1
59.58, 159.63, 159.70, 159.75.
+
MS (FAB): m/z = 761 (M + 1).
(
–)-(3-Methoxyphenyl)(phenyl)methanol (4h)
2
0
+
Colorless oil; [a]D –13 (c 2.46, THF). The ee was determined by
HPLC analysis (Daicel chiralcel OB-H, hexane–i-PrOH).
HRMS: m/z [M – BH
3
] calcd for C43
H
56
O
7
P
2
: 746.3501; found:
746.3500.
–
1
IR (neat): 3417 cm .
(
R)-1-Naphthyl(phenyl)methanol (4a) by Asymmetric Phenyla-
tion with Borane Complex 8
To a stirred soln of RhCl ·3 H O (2.90 mg, 0.011 mmol) in DME–
1
H NMR (CDCl ): d = 2.21 (br s, 1 H), 3.78 (s, 3 H), 5.81 (s, 1 H),
3
6
.77–6.84 (m, 1 H), 6.92–6.99 (m, 2 H), 7.21–7.40 (m, 6 H).
3
2
1
3
H O (5:1, 1.2 mL) were added borane complex 8 (8.4 mg, 0.011
mmol), NaOt-Bu (70.7 mg, 0.736 mmol), PhB(OH) (89.8 mg,
0
C NMR (CDCl ): d = 55.24, 76.16, 112.07, 112.92, 118.82,
2
3
1
26.43, 127.49, 128.38, 129.39, 143.56, 145.34, 159.62.
2
.736 mmol), and 1-naphthaldehyde (3a, 57.5 mg, 0.368 mmol) at
+
MS (EI): m/z = 214 (M , base peak), 135, 109, 77.
r.t. The mixture was stirred at 100 °C for 48 h under argon, allowed
Anal. Calcd for C H O : C, 78.48; H, 6.59. Found: C, 78.79; H,
to cool, diluted with H O and extracted with EtOAc. The combined
14
14
2
2
6.80.
extracts were washed with brine, dried (Na SO ), and concentrated.
2
4
The residue was purified by column chromatography (silica gel,
EtOAc–hexane, 1:19 to 1:9) to give 4a as a colorless oil; yield: 70.9
mg (82%); 63% ee (Daicel chiralcel OD-H, hexane–i-PrOH). The
(
R)-Neobenodine (7)
To a stirred soln of enantiomerically pure (R)-phenyl(4-tolyl)meth-
anol [4c, >99% ee after recrystallization (EtOAc–hexane), 355 mg,
4
a
spectral data of 4a were comparable to those reported.
1.79 mmol] and 2-chloro-N,N-dimethylacetamide (239 mg, 1.97
mmol) in THF (6.0 mL) was added NaH (60% in mineral oil, 78.8
mg, 1.97 mmol) at 0 °C. The mixture was stirred at r.t. for 3 h,
Acknowledgement
quenched with H O, and extracted with EtOAc. The combined ex-
2
We thank the Ministry of Education, Culture, Sports, Science and
Technology, Japan for support. K.K. was financially supported by
Takeda Science Foundation.
tracts were washed with brine, dried (Na SO ), and concentrated.
2
4
The residue was purified by column chromatography (silica gel,
EtOAc–hexane, 1:14 to 1:1) to give N,N-dimethyl-2-[phenyl(4-
tolyl)methoxy]acetamide (472 mg). The acetamide was dissolved in
Synthesis 2006, No. 22, 3809–3814 © Thieme Stuttgart · New York

3814
T. Arao et al.
PAPER
References
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(
(
(
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(
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(
(
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2
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(
(
(
2
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4
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7
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(
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Synthesis 2006, No. 22, 3809–3814 © Thieme Stuttgart · New York