Gold(I)-catalyzed asymmetric desymmetrization of meso-alkynyl diols and kinetic resolution of the corresponding DL-diols: Effects of celite filtration and silver salts

Article abstract of DOI:10.1002/chem.201405889

The asymmetric desymmetrization of meso-2-alkynylbenzenediols through the use of a combination of axially chiral diphosphine(AuCl)₂ precatalysts and silver salt co-catalysts gave optically active isochromene compounds with high enantioselectivities in good yields. The corresponding dl-diol isomers underwent efficient kinetic resolution to give the cyclized isochromenes and recovered diols with high enantioselectivities under similar conditions. The high reactivity and selectivity in the desymmetrization of the meso-diols is independent of the combination of axially chiral diphosphine(AuCl)₂ precatalyst and silver salt co-catalyst, whereas the corresponding tricarbonylchromium complexes of alkynylbenzenediols were affected by the combination of the diphosphine(AuCl)₂ and silver salt. The reactivity was largely dependent on the nature of the gold(I) species.

Full text of DOI:10.1002/chem.201405889

DOI: 10.1002/chem.201405889
Full Paper
&
Asymmetric Synthesis
Gold(I)-Catalyzed Asymmetric Desymmetrization of meso-Alkynyl
Diols and Kinetic Resolution of the Corresponding dl-Diols:
Effects of Celite Filtration and Silver Salts
Yumi Sota, Masaaki Yamamoto, Masato Murai, Jun’ichi Uenishi, and Motokazu Uemura*[a]
Abstract: The asymmetric desymmetrization of meso-2-alky-
nylbenzenediols through the use of a combination of axially
chiral diphosphine(AuCl)2 precatalysts and silver salt co-cata-
lysts gave optically active isochromene compounds with
high enantioselectivities in good yields. The corresponding
dl-diol isomers underwent efficient kinetic resolution to give
the cyclized isochromenes and recovered diols with high
enantioselectivities under similar conditions. The high reac-
tivity and selectivity in the desymmetrization of the meso-
diols is independent of the combination of axially chiral di-
phosphine(AuCl)2 precatalyst and silver salt co-catalyst,
whereas the corresponding tricarbonylchromium complexes
of alkynylbenzenediols were affected by the combination of
the diphosphine(AuCl)2 and silver salt. The reactivity was
largely dependent on the nature of the gold(I) species.
Introduction
zation and kinetic resolution has increased and they are con-
sidered as synthetically useful methods.[6]
The asymmetric desymmetrization reaction of highly substitut-
ed meso compounds is a powerful strategy for the synthesis of
chiral molecules with multiple stereocenters in a single opera-
tion.[1] In general, to achieve an enantioselective symmetry-
breaking synthetic operation, two enantiotopic functional
groups must be differentiated; this can be achieved by the use
of an enzymatic or nonenzymatic chiral reagent or catalyst. In
particular, numerous methods for the asymmetric desymmetri-
zation of meso-diols have been developed. Most of these reac-
tions involve an enantiotopic monoprotection achieved
through the use of acylation or silylation reagents,[2] but de-
symmetrization reactions accompanied by ring formation be-
tween a hydroxy and other functional groups in the substrate
are limited.[3] The asymmetric desymmetrization of meso com-
pounds with heterocyclic ring formation between a heteroatom
and a carbonÀcarbon unsaturated bond would be an impor-
tant tool for the construction of optically active heterocyclic
natural products. Kinetic resolution, including the thermody-
namic kinetic resolution of dl compounds, has also been es-
tablished as a strategy for the asymmetric synthesis of enantio-
merically pure compounds.[4] A number of kinetic resolutions
of mono- and diol compounds have been reported in connec-
tion with techniques for improving efficiency.[4j,5] Following ex-
tensive studies and developments in asymmetric reactions, the
number of strategies available for metal-catalyzed desymmetri-
The number of applications of gold(I) complexes as homo-
geneous catalysts for organic transformations has increased
significantly over the past decade.[7] Moreover, effective gold(I)-
catalyzed enantioselective reactions based on the p activation
of carbonÀcarbon multiple bonds have been developed.[8] Al-
though the AuI cation displays superior reactivity with regard
to the electrophilic activation of unsaturated carbonÀcarbon
bonds, stereoinduction based on gold catalysis has been con-
sidered extremely challenging. In particular, the gold(I)-cata-
lyzed asymmetric addition of heteroatoms and carbon nucleo-
philes to allenes[8b,h–j,9] and allylic alcohols[10] has been achieved
with high enantioselectivity. In the nucleophilic addition of het-
eroatoms to an alkyne bond, for the generation of chiral com-
pounds, the chirality should be created at a position other
than the heterocyclic part.[11] The gold-catalyzed asymmetric
desymmetrization of a few meso substrates with an alkyne
bond has been reported with moderate-to-excellent enantiose-
lectivities.[12] With a view to generating chiral compounds by
nucleophilic addition to alkyne bonds, we recently reported
that gold(I)-catalyzed asymmetric induction of planar chirality
by intramolecular hydroalkoxylation and hydroamination of
the alkyne bond of prochiral alkynylbenzene chromium com-
plexes gave planar chiral chromium complexes of 1H-isochro-
mene or 1,2-dihydroisoquinoline with excellent enantioselecti-
vity.[12c,d] As a further extension of this gold(I)-catalyzed asym-
metric nucleophilic addition of a heteroatom to an alkyne
bond, we would like to report herein the details of the desym-
metrization of meso diols of 2-alkynyl-substituted benzene de-
rivatives and the kinetic resolution of the corresponding dl-
diols for the construction of chiral 1H-isochromene derivatives.
[a] Y. Sota, M. Yamamoto, M. Murai, Prof. Dr. J. Uenishi, Prof. Dr. M. Uemura
Kyoto Pharmaceutical University
Yamashina, Kyoto 607-8412 (Japan)
E-mail: muemura@mb.kyoto-phu-ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405889.
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Results and Discussion
Table 1. Desymmetrization of meso-2-alkynylbenzenediols 1.
The meso- and dl-2-alkynylben-
zenediols used as starting mate-
rials were easily prepared from
2-bromoisophthalaldehyde[13]
(see the Supporting Informa-
tion). The asymmetric cyclization
reactions of meso-2-alkynylben-
zenediols 1 occurred readily by
using a combination of an axially
chiral diphosphine(AuCl)2 preca-
meso-1
R1, R2
Gold catalyst 2
AgX
T [8C]
t [min]
Yield of 3 [%]
ee of 3 [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1aa
1aa
1aa
1aa
1ac
1ba
1ba
1ba
1ba
1ba
1ba
1bb
1bc
1bd
1ca
1ca
1ca
1ca
1cc
Me, Me
Me, Me
Me, Me
Me, Me
Me, Ph
nBu, Me
nBu, Me
nBu, Me
nBu, Me
nBu, Me
nBu, Me
nBu, iPr
nBu, Ph
nBu, Bn
Ph, Me
Ph, Me
Ph, Me
Ph, Me
Ph, Ph
2a
2a
2a
2b
2b
2a
2a
2a
2b
2c
2c
2a
2a
2a
2a
2a
2a
2c
2a
AgNTf2
AgNTf2
AgOTf
AgNTf2
AgNTf2
AgNTf2
AgSbF6
AgOTf
AgOTf
AgBF4
AgNTf2
AgNTf2
AgOTf
AgOTf
AgNTf2
AgSbF6
AgOTf
AgOTf
AgOTf
0
À20
À20
À20
À30
À20
À20
À20
À20
À20
À20
À20
À30
À30
À20
À20
À20
À20
À30
10
15
15
15
30
15
15
15
10
15
15
30
40
40
15
15
15
15
60
80
90
99
83
92
99
99
93
97
99
99
71
99
99
99
99
99
92
84
80
92
91
93
84
92
93
93
96
95
96
98
99
97
99
98
97
99
95
talyst
2 and a silver salt in
CH2Cl2. The meso diol compound
1aa with a methyl substituent at
both the alkyne terminal and
benzylic positions was treated
with 5 mol% [(R)-binap(AuCl)2]
(2a) and 10 mol% AgNTf2 in
methylene chloride at 08C for
10 min to give the 6-endo-dig[14]
cyclization product (+)-1,3-di-
methyl-5-(a-hydroxyethyl)-1H-
isochromene (3aa) in a yield of
80% with 80% ee (Table 1,
entry 1). The enantioselectivity
was increased to 92% ee by
using a temperature of À208C (entry 2). The meso-diols 1ba–
bd with an n-butyl substituent at the alkyne terminal position
gave the corresponding cyclization products with excellent
enantioselectivities (entries 6–14). The meso-diols 1 with steri-
cally bulky iPr, phenyl, or benzyl groups at the benzylic posi-
tions gave the cyclization products with excellent enantioselec-
tivities, although a slightly longer reaction time was required
(entries 12–14 and 19). The counter anions of the silver salts
did not have a significant effect on the reactivity and selectivi-
ty of the gold-catalyzed desymmetrization of the meso-diols.
Any combination of axially chiral diphosphine(AuCl)2 and silver
salt resulted in excellent enantioselectivity. Thus, meso-2-alky-
nylbenzenediols 1 underwent asymmetric desymmetrization
through the use of a combination of an axially chiral diphos-
phine(AuCl)2 precatalyst 2 and a silver salt to give optically
active 1H-isochromene derivatives[15] with high enantioselectiv-
ities in good yields.
Scheme 1. Synthesis of authentic 1,3-dimethyl-5-(a-hydroxyethyl)-1H-iso-
chromene. Reagents and conditions: MeLi, ether (94%); b) Me3SiCl, imida-
zole, Et3N, THF (95%); c) nBuLi, THF, À78 to À48C, then DMF (63%); d) 1-
hexyne, [Pd(PPh3)2Cl2], Et3N, THF (75%); e) hn, air, diethyl ether; f) TBAF, THF
(70% two steps); g) (CH2OH)2, p-TsOH, benzene (99%); h) [PPh3AuNTf2],
CH2Cl2 (83%); i) MeLi, THF (78%)
The absolute configuration of the cyclized (+)-isochromene
compound 3ba (R1 =nBu, R2 =Me) obtained by the desymmet-
rization of meso-diol 1ba was determined to be (R)-1-[(S)-3-
butyl-1-methyl-1H-isochromen-5-yl]ethanol by comparison
with an authentic compound prepared from a planar chiral
arene chromium complex (Scheme 1). Enantiomerically pure
(À)-(R)p-tricarbonyl(2-chlorobenzaldehyde)chromium (4)[16] was
converted stereoselectively into the (À)-(R)-1-(2-chlorophen-
yl)ethanol chromium complex 5 by treatment with MeLi. Pro-
tection with Me3SiCl followed by ortho lithiation and quench-
ing with DMF gave the (+)-formylated arene chromium com-
plex 6 in a good overall yield. Sonogashira coupling of 6 with
hex-1-yne, demetalation in air, and subsequent cyclization with
an achiral gold reagent gave (À)-(R)-3-butyl-1-methyl-1H-iso-
chromene-5-carbaldehyde (7). The treatment of 7 with MeLi af-
forded an easily separable 1:1 mixture of isochromene deriva-
tives 8A and 8B. The absolute configuration of 8A was as-
signed as an antipode of the asymmetric desymmetrization
product 3ba on the basis of chiral HPLC behavior and the opti-
cal rotation value.
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Table 2. Kinetic resolution of dl-alkynylbenzenediols dl-9.
dl-9
R1, R2
Gold catalyst 2
AgX
T [8C]
t [min]
Yield [%]
ee [%]
Yield [%]
ee [%]
C [%][a]
S[a]
of 10
of (S,S)-10
of (S,S)-9
of (S,S)-9
1
2
3
4
5
6
7
8
9
10
11
12
13
9aa
9aa
9ba
9ba
9ba
9ba
9bc
9bc
9bd
9ca
9ca
9ca
9ca
Me, Me
Me, Me
nBu, Me
nBu, Me
nBu, Me
nBu, Me
nBu, Ph
nBu, Ph
nBu, Bn
Ph, Me
Ph, Me
Ph, Me
Ph, Me
2a
2b
2b
2a
2a
2b
2b
2a
2b
2a
2a
2b
2b
AgOTf
AgOTf
AgNTf2
AgOTf
AgNTf2
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgNTf2
AgOTf
AgNTf2
À30
À30
À30
À30
À30
À30
À30
À30
À30
À20
À20
À20
À15
10
30
40
10
60
50
30
90
30
60
40
40
50
45
47
55
45
48
47
55
42
48
45
40
48
45
94
97
61
94
79
93
80
91
95
90
87
94
97
47
47
32
47
45
47
42
47
46
48
49
47
53
91
91
99
91
79
93
99
91
99
93
65
98
80
49
46
62
49
50
50
55
50
51
51
43
51
45
105
170
22
101
20
94
39
67
201
67
28
146
160
[a] Values of C and S were calculated by the method of Kagan and Fiaud.[17] S: stereoselectivity factor; S=ln[1ÀC(1+ee)]/ln[1ÀC(1Àee)].
We also developed the gold(I)-catalyzed asymmetric reaction
of the corresponding dl-alkynylbenzenediols leading to their
kinetic resolution (Table 2). Racemic diol 9aa with a methyl
substituent at both the benzylic and alkyne terminal positions
was treated with the [(R)-binap(AuCl)2] precatalyst (2a) and
AgOTf as co-catalyst at À308C in methylene chloride to give
the (+)-isochromene compound 10aa in a yield of 45% with
94% ee. Recovered (À)-diol 9aa was obtained in a yield of
47% with 91% ee (entry 1). The selectivity S value was in-
creased by using the sterically bulky [(R)-xylylbinap(AuCl)2]
(entry 2). With dl-diol 9ba with n-butyl at the alkyne position,
the use of noncoordinating AgOTf as co-catalyst gave superior
results than the use of the weakly coordinating AgNTf2 as co-
catalyst (entries 3 vs 6 and 4 vs 5). dl-Diol 9ca with a phenyl
at the alkyne terminal position showed high selectivity with
the combination of [(R)-xylylbinap(AuCl)2] and AgOTf at À208C
(entry 12). The S values of the kinetic resolution were satisfac-
tory. Thus, kinetic resolution through the use of a combination
9
with the S,S configuration with good-to-excellent
selectivities.
It has generally been accepted that [L-Au]+XÀ species gener-
ated in situ by chloride abstraction with silver salts (AgX) from
neutral [L-Au]Cl complexes is actually
p acidic towards
carbonÀcarbon multibond activation in gold(I)-promoted reac-
tions. Intriguingly, the reactivities of the gold catalysts generat-
ed in situ in some cases differ dramatically to the Celite-filtered
gold catalysts.[18] We therefore examined the effect of Celite fil-
tration of the gold species on the desymmetrization of meso-
diols 1 (Figure 1). The reactivity reduced dramatically by the fil-
tration of the in situ generated gold catalyst through Celite
of (R)-axially chiral diphosphine(AuCl)2 precatalyst
2 and
a silver salt took place with high efficiency to give optically
active 1H-isochromene derivatives along with recovered opti-
cally enriched diols with excellent enantioselectivities. Both
compounds are useful as precursors of biologically active het-
erocyclic compounds.
The absolute configuration of the cyclized (+)-isochromene
derivative 10ba obtained by the gold-catalyzed kinetic resolu-
tion of dl-alkynyl diol 9ba was determined as (R)-1-[(R)-3-
butyl-1-methyl-1H-isochromen-5-yl]ethanol by comparison of
its optical rotation value and chiral HPLC behavior with au-
thentic compound 8B. Thus, the kinetic resolution of dl-diol
compounds 9 through the use of a combination of (R)-axially
chiral diphosphine(AuCl)2 precatalyst 2 and a silver salt co-cata-
lyst gave R,R-configured isochromenes 10 and recovered diols
Figure 1. Effect of Celite filtration on the reactivity of the gold catalysts 2.
Source of chiral gold catalyst and reaction conditions: A: In situ preparation
from gold precatalyst (5 mol%) and AgX (10 mol%), À208C, 20 min. B: Filtra-
tion of the in situ formed catalyst through Celite, À208C, 60 min. C: Addi-
tion of AgX (10 mol%) to the filtrate, À208C, 60 min.
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(conditions B) to give yields of less than 10%. The sequential
addition of the silver salt to the Celite filtrate (conditions C) re-
sulted in the re-activation of the gold catalyst, although
a slightly longer reaction time was needed. Because the Celite
filtration removed AgCl, the contrasting results suggest that
the silver cations are the crucial “activation factor” for the [L-
Au]+ species. Interestingly, the enantioselectivity increased fol-
lowing the addition of the silver salt to the Celite filtrate of the
in situ generated gold species. Moreover, the reaction with the
re-activated gold species gave a constant yield, even though
the yields obtained with the in situ generated gold catalyst
varied somewhat. Therefore we suggest that the re-activated
gold catalyst obtained by the addition of silver salt to the fil-
trate passed through Celite should be employed for an im-
provement of the enantioselectivity because undesirable active
gold species should be removed.
Table 3. Gold-catalyzed asymmetric desymmetrization of meso-diol 11.
meso-11 Conditions[a] Yield of
d.r. (12) ee of 12 (major/
minor) or 13 [%]
(A or C)
12/13 [%]
1
2
3
4
5
6
11 a
11 a
11 b
11 b
11 c
11 c
A
C
A
C
A
C
84/0
0/83
94/0
0/91
92/0
0/75
–
17
–
59/61
40
55/50
50
4:1
4:1
Furthermore, we examined the desymmetrization of the
meso-diols 11 with the hydroxymethyl groups at ortho posi-
tions at both ends of the 1,2-diphenylethyne skeleton, and the
effect of Celite filtration on the reactivity (Table 3). The reac-
tions of diols 11 b and 11 c with the in situ prepared gold cata-
lyst from [(R)-xylylbinap(AuCl)2] and AgOTf (conditions A) gave
diastereomeric spiroketal compounds 12 in good yields. How-
ever, the enantioselectivities of the two spiro compounds were
moderate, in contrast to the high enantioselectivities obtained
with meso-2-alkynylbenzenediols 1 shown in Table 1. meso-
Diols 11 showed different reactivity with the active gold spe-
cies under conditions C than with the in situ generated gold
catalyst. Thus, the reaction with the re-activated gold species
(conditions C) afforded monocyclized compounds 13 without
the formation of spiroketal compounds. These results have
been attributed to the removal
[a] Conditions: A: 5 mol% [(R)-xylylbinap(AuCl)2] + 10 mol% AgOTf; C:
Celite filtration of in situ prepared catalyst and then addition of 10 mol%
AgOTf. For more details of the conditions, see Figure 1.
(entry 2). At room temperature, the yield increased to 40%
with an ee of 40%. Similarly, the desymmetrization of the 2-al-
kynyl-1,3-bis(hydroxymethyl)benzene chromium complex 14
with monophosphine gold catalysts resulted in lower selectivi-
ty (entries 6–9). Thus, the diphosphine gold species are highly
reactive catalysts giving excellent enantioselectivity, whereas
the monophosphine gold catalyst and AgNTf2 shows low
reactivity in the desymmetrization of meso-diols. In addition,
of an acidic species by Celite fil-
tration.
Table 4. Cyclization of the meso-diols 1ba and 14 with monophosphine gold catalysts.
As the gold catalysts obtained
by chloride abstraction of axially
chiral diphosphine(AuCl)2 preca-
talysts with a silver salt co-cata-
lyst were excellent catalytic spe-
cies for the desymmetrization of
meso-diols, we next studied the
efficacy of monophosphine gold
catalysts in the cyclization of
meso-diols (Table 4). The cycliza-
tion of 1ba with isolated achiral
[PPh3AuNTf2] gave a yield of only
5%. Similarly, the reaction with
the gold species generated in
situ from [PPh3AuCl] and AgNTf2
resulted in a yield of only 10%
(Table 4, entry 1). With the
mono-dechlorinated gold(I) cat-
ionic species obtained from
5 mol% [(R)-binap(AuCl)2] (2a)
and 5 mol% AgNTf2, the yield of
the cyclization product obtained
at 08C was 20% with 54% ee
Subst.
[Au] catalyst
T [8C]
t [h]
Yield of
3ba or 15 [%]
ee [%]
1
2
3
4
5
6
7
8
9
1ba
1ba
1ba
1ba
14
14
14
14
14
[PPh3AuCl] (10 mol%)/AgNTf2 (10 mol%)
2a (5 mol%)/AgNTf2 (5 mol%)
16a (5 mol%)/AgNTf2 (5 mol%)
16b (5 mol%)/AgNTf2 (5 mol%)
2a (5 mol%)/AgNTf2 (5 mol%)
16a (10 mol%)/AgNTf2 (10 mol%)
16b (10 mol%)/AgNTf2 (10 mol%)
17a (10 mol%)/AgNTf2 (10 mol%)
17b (10 mol%)/AgNTf2 (10 mol%)
À20
0
0
0
RT
0
0
0
0
1
1
2
2
1
2
2
1
1
10
20
25
36
40
25
36
22
40
–
54
0
0
40
0
0
0
0
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mononuclear gold(I) cationic species derived from phosphor-
amidite ligands also showed low reactivity and selectivity.
This low reactivity of the monophosphine gold catalyst was
only recognized in compounds having two free hydroxy
groups at both ortho positions in compounds of type 1. The
reactions of alkynylbenzene mono-alcohols in the presence of
the monophosphine gold catalyst gave good yields. Thus, in
the reactions of meso-diols with a monophosphine gold cata-
lyst, one of the free hydroxy groups interferes with the coordi-
nated gold metal to decrease the electrophilicity of the alkyne
bond. On the other hand, one of the gold atoms in the dech-
lorinated species generated from diphosphine(AuX)2 coordi-
nates to the alkyne bond and the other gold atom interacts
with the free hydroxy group.
Experimental Section
General: All manipulations involving organometallics were carried
out under an atmosphere of argon or nitrogen using inert gas/
vacuum double-manifold techniques. Diethyl ether and tetrahydro-
furan were distilled from sodium/benzophenone ketyl immediately
before use. Methylene chloride was distilled over P2O5 before use.
General procedure for the gold-catalyzed asymmetric desym-
metrization of meso-diols 1: A mixture of axially chiral [(R)-biary-
l(AuCl)2] 2 (0.006 mmol) and a silver salt (0.012 mmol) in CH2Cl2
(1 mL) was stirred at room temperature for 10 min under nitrogen.
Silver chloride precipitated from solution during the time. The re-
action mixture was cooled to À208C and then a solution of meso-
diol 1 (0.06 mmol) in CH2Cl2 (2.0 mL) was added to the above reac-
tion mixture by syringe. After stirring for 15 min, diethyl ether
(5 mL) was added to the reaction mixture, which was then filtered
through a short layer of silica gel. Concentration of the organic
layer under reduced pressure and purification by silica gel column
chromatography (10% diethyl ether in hexane) gave cyclization
product 3.
In this way the gold species derived by the abstraction of
two chlorides from the axially chiral [biaryl(AuCl)2] precatalyst
with a silver salt co-catalyst is the essential active species for
high reactivity and enantioselectivity in the desymmetrization
of meso-2-alkynylbenzenediols. Recently, the interference of
silver metal in gold catalysis was demonstrated by the isolation
of chloride-bridged trimetallic dicationic compounds.[19] Fur-
thermore, a diaurated structure as reaction intermediate was
isolated in the intramolecular hydroarylation of allenes.[20] Un-
fortunately, we could not isolate the reaction intermediate in
the asymmetric desymmetrization of meso-diols 1 through the
use of a combination of axially chiral diphosphine(AuCl)2 with
a silver salt as co-catalyst in the presence of a proton scaveng-
er. Moreover, (phosphine)gold(I) hydrate complexes were iso-
lated by the treatment of [Ar3PAuCl] with AgOTf in wet CH2Cl2,
and are proposed as the key species for the gold-catalyzed re-
action.[21] However, the structures of the real active gold spe-
cies and the re-activated gold species following the addition of
a silver salt to the Celite filtrate are still unclear and remain to
be elucidated.
(R)-1-[(S)-1,3-Dimethyl-1H-isochromen-5-yl]ethanol (3aa): Prod-
uct 3aa was obtained as a colorless liquid. Yield: 99%; [a]2D0 = +
1
23.2 (c=0.42 in CHCl3); H NMR (400 MHz, CDCl3): d=7.38 (d, J=
7.6 Hz, 1H), 7.14 (t, J=7.6 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 5.83
(brs, 1H), 5.18 (q, J=6.5 Hz, 1H), 5.14 (q, J=6.5 Hz, 1H), 1.96 (d,
J=0.9 Hz, 3H), 1.63 (brs, 1H), 1.58 (d, J=6.5 Hz, 3H), 1.49 ppm (d,
J=6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=154.2, 137.3, 131.8,
128.0, 126.0, 124.2, 122.6, 97.1, 74.4, 66.9, 24.1, 20.5, 19.8 ppm; IR
(CHCl3): n˜ =3386, 1649 cmÀ1; MS (EI, 70 eV): m/z (%): 204 (33) [M]+,
189 (100) [MÀCH3]+, 171 (53) [MÀCH3ÀH2O]+; HRMS: calcd for
C13H16O2: 204.1150; found; 204.1152; HPLC (Chiralpak OD-H), UV
detector 254 nm, Hexane/iPrOH=95:5; flow rate 0.30 mLminÀ1, re-
tention time=25.4, 29.3 min (major isomer); 91% ee.
(R)-[(S)-3-Methyl-1-phenyl-1H-isochromen-5-yl](phenyl)methanol
(3ac): Yield: 99% yield; m.p. 46–478C; [a]2D0 = +11.4 (c=0.45 in
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.40–7.27 (m, 10H), 7.33 (d,
J=7.6 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 6.09
(s, 1H), 6.05 (s, 1H), 5.89 (s, 1H), 2.16 (brs, 1H), 1.93 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=154.9, 143.2, 140.0, 135.2, 130.0,
129.5, 128.7 (2C), 128.5 (2C), 128.5, 128.0 (2C), 127.7, 126.7 (2C),
125.7, 125.2, 98.3, 80.4, 72.7, 20.5 ppm; IR (CDCl3): n˜ =3421,
1648 cmÀ1; MS (EI, 70 eV): m/z (%): 328 (100), [M]+, 251 (23)
[MÀC6H5]+; HRMS: calcd for C23H20O2: 328.1463; found: 328.1467;
elemental analysis calcd (%) for C23H20O2: C 84.12, H 6.14; found: C
84.00, H 6.28; HPLC (Chiralpak AS-H), UV detector 254 nm, Hexane/
iPrOH=95:5, flow rate 0.5 mLminÀ1, retention time=28.4, 32.1 min
(major isomer); 84% ee.
Conclusion
The catalytic asymmetric desymmetrization of meso-2-alkynyl-
benzenediols has been achieved through the use of a combina-
tion of an axially chiral diphosphine(AuCl)2 precatalyst and
a silver salt co-catalyst to give optically active 1H-isochromene
derivatives with high enantioselectivities in good yields. More-
over, the corresponding dl-diols efficiently underwent kinetic
resolution to afford isochromene derivatives with high enantio-
selectivities along with the recovery of highly optically en-
riched alkynylbenzenediols under similar conditions. The pres-
ence of silver salts was very important for high reactivity and
enantioselectivity. Thus, Celite filtration of the gold catalysts
obtained by chloride abstraction from diphosphine(AuCl)2 pre-
catalysts by silver salts led to decreased reactivity and selectivi-
ty. The re-activated gold catalysts obtained by the addition of
a silver salt to the filtrate proved to be superior species to the
original in situ generated catalyst species in terms of selectivity
and reactivity. Monophosphine gold species showed low reac-
tivity in these reactions.
General procedure for the kinetic resolution of dl-1,1’-(2-hexy-
1-ynyl-1,3-phenylene)diethanol (9ba): A mixture of [(R)-xylylbina-
p(AuCl)2] (2b; 19.5 mg, 12.3 mmol) and AgOTf (6.3 mg, 24.3 mmol)
in CH2Cl2 (12 mL) was stirred at room temperature for 10 min
under nitrogen. Silver chloride precipitated from solution during
this time. A solution of dl-diol 9ba (30.0 mg, 0.123 mmol) in
CH2Cl2 (12 mL) was added to the reaction mixture at À308C and
the mixture was stirred for 50 min. The reaction mixture was then
filtered through a small amount of silica gel and the filtrate was
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography with 20% diethyl ether in
hexane as eluent to give cyclized compound 10ba (14.7 mg, 49%)
and (S,S)-diol 9ba (14.4 mg, 47%).
(R)-1-[(R)-3-Butyl-1-methyl-1H-isochromen-5-yl]ethanol (10ba):
Colorless liquid; [a]D20 = +24.1 (c=0.10 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.37 (d, J=7.6 Hz, 1H), 7.14 (t, J=7.6 Hz, 1H),
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6.94 (d, J=7.6 Hz, 1H), 5.83 (s, 1H), 5.16 (q, J=6.5 Hz, 1H), 5.14 (q,
J=6.5 Hz, 1H), 2.21 (t, J=7.3 Hz, 2H), 1.78 (br, 1H), 1.61–1.53 (m,
2H), 1.58 (d, J=6.5 Hz, 3H), 1.50 (d, J=6.5 Hz, 3H), 1.43–1.34 (m,
2H), 0.94 ppm (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d=
157.9, 137.4, 132.1, 128.0, 125.9, 124.2, 122.1, 96.5, 74.3, 66.9, 34.2,
29.3, 24.0, 22.5, 19.7, 14.0 ppm; IR (CDCl3): n˜ =3475, 1652 cmÀ1; MS
(EI, 70 eV): m/z (%): 246 (32, [M]+, 231 (100) [MÀCH3]+; HRMS:
calcd for C16H22O2: 246.1620; found: 246.1624; HPLC (Chiralcel OD-
H), UV detector 254 nm, Hexane/iPrOH=95:5, flow rate
0.5 mLminÀ1, retention time=14.3, 18.0 min (major isomer); 94%
ee.
Unreacted
(1S,1’S)-1,1’-(2-hex-1-ynyl-1,3-phenylene)diethanol
(9ba): Colorless crystals; m.p. 94–958C; [a]2D0 =À77.7 (c=0.71 in
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.45 (d, J=7.6 Hz, 2H), 7.34
(t, J=7.6 Hz, 1H), 5.34 (q, J=6.6 Hz, 2H), 2.51 (t, J=7.0 Hz, 2H),
2.12 (brs, 2H), 1.67–1.60 (m, 2H), 1.53–1.45 (m, 2H), 1.52 (d, J=
6.6 Hz, 6H; Me), 0.97 ppm (t, J=7.3 Hz, 3H; Me); 13C NMR
(100 MHz, CDCl3): d=147.7 (2 C), 128.4, 123.5 (2 C), 118.5, 101.5,
75.8, 68.6 (2 C), 30.9, 23.9 (2 C), 22.2, 19.50, 13.7 ppm; IR (CHCl3):
n˜ =3368, 2226 cmÀ1; MS (EI, 70 eV): m/z: 246 (9) [M]+, 189 (29)
[MÀC4H9]+, 153 (100) [MÀ2H2OÀC4H9]+; HRMS: calcd for C16H22O2:
246.1620; found: 246.1627; elemental analysis calcd (%) for
C16H22O2: C 78.01, H 9.00; found: C 78.11, H 8.73; HPLC (Chiralpak
AD-H), UV detector 254 nm, Hexane/iPrOH=90:10, flow rate
1.0 mLminÀ1, retention time=10.1, 16.9 min (major isomer); 91%
ee.
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This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Keywords: asymmetric synthesis · desymmetrization · gold ·
kinetic resolution · silver
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Received: October 30, 2014
Published online on && &&, 0000
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FULL PAPER
&
Asymmetric Synthesis
Y. Sota, M. Yamamoto, M. Murai,
J. Uenishi, M. Uemura*
&& – &&
Gold(I)-Catalyzed Asymmetric
Improved enantioselection: The
sponding dl isomers undergo efficient
kinetic resolution under similar condi-
tions to give cyclized isochromenes and
recovered diols with high enantioselec-
tivities, respectively.
Desymmetrization of meso-Alkynyl
Diols and Kinetic Resolution of the
Corresponding dl-Diols: Effects of
Celite Filtration and Silver Salts
gold(I)-catalyzed asymmetric desymmet-
rization of meso-2-alkynylbenzenediols
gives optically active isochromene deriv-
atives with high enantioselectivity in
good yields (see scheme). The corre-
&
&
Chem. Eur. J. 2015, 21, 1 – 8
www.chemeurj.org
8
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!