Kinetic resolution of P-Chirogenic compounds by palladium-catalyzed alcoholysis of vinyl ethers

Article abstract of DOI:10.1002/adsc.200900304

The palladium-catalyzed asymmetric alcoholysis of vinyl ethers of P-chirogenic compounds has been achieved. The kinetic resolution of aryl tert-butyl(2-vinyloxyaryl)phosphinates was catalyzed by palladium/chiral diamine complexes with high selectivities (

Full text of DOI:10.1002/adsc.200900304

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DOI: 10.1002/adsc.200900304
Kinetic Resolution of P-Chirogenic Compounds by Palladium-
Catalyzed Alcoholysis of Vinyl Ethers
Hisashi Itoh,a Eiji Yamamoto,a Shigeyuki Masaoka,a Ken Sakai,a
and Makoto Tokunagaa,*
a
Department of Chemsitry, Kyushu University, Fukuoka 812-8581, Japan
Fax : (+81)-92-642-7528; e-mail: mtok@chem.kyushu-univ.jp
Received: April 29, 2009; Published online: July 16, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900304.
Abstract: The palladium-catalyzed asymmetric alco-
holysis of vinyl ethers of P-chirogenic compounds
has been achieved. The kinetic resolution of aryl
tert-butyl(2-vinyloxyaryl)phosphinates was catalyzed
by palladium/chiral diamine complexes with high
selectivities (krel: 12–196).
talysis. We have developed the first example of an
asymmetric alcoholysis of vinyl ethers catalyzed by
Pd-chiral diamine (1a) complexes.[7d] The kinetic reso-
lution of axially chiral compounds has been achieved.
In our recent study, the phosphoryl (PO) group was
found to be an efficient directing group and mono-
phosphoryl, monovinyl derivatives of axially chiral
diols underwent kinetic resolution in high selectivi-
ty.[7g]
Keywords: alcoholysis; chirality; kinetic resolution;
phosphorus
In the present study, we have extended this strategy
to P-chiral compounds which have been considered as
difficult targets in the asymmetric synthesis. We di-
rected our attention to phosphinate derivatives having
Introducing chirality at a phosphorus atom is of par- an o-vinyloxyphenyl group as a P-chirogenic sub-
ticular importance because chirogenic phosphorus strate.[8] This class of compounds has been used as
centers are common partial structures of a variety of chelate ligands,[8d] parts of crown ethers,[8e,g,i] precur-
functional molecules, including chiral ligands for sors of phosphachromones[8g] and biocides.[8c]
asymmetric catalysis[1] and bioactive compounds such
The substrates 2 were synthesized from tert-butyl-
as herbicides,[2a] pesticides,[2b] neurotoxins,[2c] anti- phosphonic dichloride by diphenyl ester formation,
tumor agents[2d] and modified oligonucleotides.[2e] In isomerization of one ester group to form the phosphi-
spite of the significance of the P-chirogenic com- nate by ortho-mono-lithiation,[8a,b,f,i] and then vinyla-
pounds, only limited numbers of methodologies to ap- tion[9] (Scheme 1). A P-chirogenic compound 2a (R=
proach them have been developed. The most classical H) was chosen for the test of the reaction.
method is fractional crystallization of diastereomeric
Asymmetric alcoholysis of 2a was examined with a
salts.[3] Later, enzymatic resolution by hydrolysis[4a] or Pd catalyst system employing ligands 1a and 1b,
esterification,[4b] stereoselective synthesis[5a–d] and cat- which have a cyclohexanediamine backbone. How-
alytic asymmetric synthesis including desymmetriza-
ACHTUGNRTNEeNUNG ver, only moderate selectivities (krel =11 and 10)
tion with Li-sparteine catalysts,[5e] organocatalysts,[5f] were observed (Table 1, entries 1 and 2). The tetra-
Rh-catalyzed [2+2+2]cyclization,[5g] and cross-cou- phenylphenyl substituent[7d,g,10] was not effective in
pling of R2PH with ArI[5h,i] have been developed. Re- this case. When the diamine backbone was changed
cently, an interesting method based on the Appel re- to diphenylACTHNUTRGNEUeGN thanediamine (1c), a higher selectivity
action was reported.[5j] This process realized a dynam- (krel =19) and catalytic activity were achieved
ic kinetic resolution,[6] but the observed selectivities (entry 3). On introducing a bulky substituent at the
were moderate (max. 80% ee) and a stoichiometric meta-position of the N-phenyl group (1d), the krel
chiral reagent is required.
value reached 51 (entry 4). Optically active 3a (80%
Catalytic hydrolysis and alcoholysis are environ- ee) in 48% yield and unreacted 2a (99% ee) in 45%
mentally benign, practical tools for asymmetric syn- yield were obtained.
thesis.[7] However, in the field of homogeneous cataly-
The substrate generality was examined with various
sis, little progress has been made compared to bioca- P-chirogenic substrates (2b–j). These were synthe-
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Adv. Synth. Catal. 2009, 351, 1796 – 1800

Kinetic Resolution of P-Chirogenic Compounds by Palladium-Catalyzed Alcoholysis
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Scheme 1.
Table 1. Kinetic resolution of a P-chirogenic compound 2a by Pd-catalyzed alcoholysis of vinyl ethers.
[d]
Entry
Ligand
t [h]
Conversion [%][a]
ee of 2[b] [%] (Yield [%])[c]
ee of 3[b] [%] (Yield [%])[c]
krel
1
2
3
4
1a
1b
1c
1d
8
8
4
4
19.6
13.4
45.1
55.3
20 (81)[e]
12 (85)[e]
67 (53)[e]
99.3 (45)
80 (16)[f]
80 (11)[f]
81 (36)[f]
80 (48)
11.0
10.1
19.2
50.8
[a]
Calculated with equation: conversion=eesub/(eesub+eepro).
Determined by HPLC analysis.
Isolated yield.
[b]
[c]
[d]
[e]
[f]
Calculated with equation: krel =ln
[1Àconv
G
A
G
(S)-2a was obtained.
(R)-3a was obtained.
sized by the same route as described in Scheme 1. (entry 2), which is similar to that of the unsubstituted
When meta-substituted phenyl esters underwent phos- one (2a). However, the m-methyl and m-dimethyl
phinate formation reaction by ortho-mono-lithiation, substrates (2b and d) gave lower krel values (12 and
only one of the two possible isomers was obtained. 19, entries 1 and 3). The p-chloro-, p-fluoro-, and m-
The m-tolyl ester afforded p-methyl-o-hydroxyphenyl- fluorophosphinate esters (2e, 2f and 2g) also afforded
phosphinate (3c), on the other hand m-halophenyl high selectivities (krel =37, 56, and 31; entries 4, 5 and
esters furnished o-halo-o-hydroxyphenylphosphinate 6). Dihalo-substituted substrates, particularly m,p-di-
(3g–j), respectively. The kinetic resolution with chloro and m-chloro-p-fluoro esters (2i and 2j) pre-
PdACHTUNGTRENNUNG(OAc)2 +1d as catalyst generally exhibited high se- sented selectivities of over 100 (krel =110, and 196; en-
lectivities (krel =12–196) (Table 2). Among the tries 8 and 9). For instance, unreacted 2i was obtained
methyl-substituted phosphinates (2b–d), the p-methyl with 99.8% ee in 45% yield. A 1-g scale reaction
substrate (2c) showed a selectivity value of krel =52 using 2a proceeded without any difficulty and essen-
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Hisashi Itoh et al.
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Figure 1. ORTEP drawing for (S)-3a (product of Table 1,
entry 4, recrystallization from hexane/diethyl ether).
A transformation of optically active 2a (>99% ee)
was carried out (Scheme 2). Hydrogenation of (R)-2a
gave an ethyl ether and ortho-lithiation to make a
À
P C bond afforded a phosphine oxide. In both cases,
the enantiomeric excesses of the products were main-
tained (>99% ee). The absolute configuration of the
tially the same selectivity was observed (krel =50, phosphine oxide was again confirmed by the X-ray
entry 10).
crystallographic analysis.
A single recrystallization of 3a (80% ee) afforded
In conclusion, we have accomplished a kinetic reso-
enantiopure (>99% ee) crystals. The absolute struc- lution of P-chirogenic vinyl ethers (2a–j) with high se-
ture of 3a obtained with (S,S)-1d/Pd catalyst was lectivities (krel up to 196) by an alcoholysis reaction
found to have the (S)-configuration by X-ray crystal- with PdACTHNUTRGENUG(N OAc)2/1d as a catalyst. These chiral com-
lographic analysis, in which the absolute structure was pounds (2 and 3) provide potential building blocks for
unambiguously determined based on the Flack pa- novel chiral ligands and bioactive compounds. Ex-
rameter (0.03) refined for the reported configuration tended studies utilizing this strategy are now under
(Figure 1).
way.
Table 2. Kinetic resolution of P-chirogenic compounds 2 via PdACTHNURGTNEUNG(OAc)2/1d-catalyzed alcoholysis.
[d]
Entry
Substrate
t [h]
Conversion [%][a]
ee of 2[b] [%] (Yield [%])[c]
ee of 3[b] [%] (Yield [%])[c]
krel
1
2
3
4
5
6
7
8
2b
2c
2d
2e
2f
2g
2h
2i
1
5
5
4
4
4
4
4
5
4
44.4
53.4
30.3
53.1
50.8
48.9
30.2
52.9
41.5
49.6
60 (46)
97 (41)
37 (62)
94 (43)
92 (47)
81 (43)
41 (65)
99.8 (45)
70 (56)
88 (52)
75 (42)
85 (50)
86 (30)
83 (43)
89 (46)
85 (48)
94 (29)
89 (51)
98 (41)
89 (48)
12.4
52.3
18.5
37.4
56.2
30.6
49.0
110
9
2j
2a
196
50.4
10[e]
[a]
Calculated with equation: conversion=eesub/(eesub+eepro).
Determined by HPLC analysis.
Isolated yield.
[b]
[c]
[d]
[e]
Calculated with equation: krel =ln
[1Àconv
N
A
ACHTUGNRTNE(NUNG 1-eepro)].
A 3.67 mmol (1.16 g) scale reaction.
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Kinetic Resolution of P-Chirogenic Compounds by Palladium-Catalyzed Alcoholysis
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Experimental Section
Typical Procedure for the Kinetic Resolution of 2a
A mixture of PdACHTUNGTRENNUNG(OAc)2 (40.5 mg, 0.180 mmol) and 1d
(205.9 mg, 0.264 mmol) in CH2Cl2 (3.5 mL) was stirred at
room temperature under air. After 1 h, the mixture was con-
centrated under reduced pressure and dried under vacuum.
To this residue was added a CH2Cl2 (anhydrous, 2.1 mL) so-
lution of 2a (1.1607 g, 3.67 mmol) and methanol (anhydrous,
1.4 mL, 35 mmol), and the mixture was stirred at 208C
under ambient atmosphere for 4 h. Silica-gel column chro-
matography was carried out to give (S)-3a (yield: 508.1 mg,
47.7% yield, 89.2% ee) and (R)-2a (yield: 598.9 mg, 51.6%
yield, 87.8% ee).
CCDC 724711 [(S)-3a] and CCDC 724712 {(S)-2-[tert-
butyl(2-ethoxyphenyl)phosphinoyl]phenol} contain the sup-
plementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Supporting Information
Additional experimental procedures and spectral data are
available as Supporting Information.
Acknowledgements
The present work is supported by a Grant-in-Aid for Global-
COE program, “Science for Future Molecular Systems” from
the Ministry of Education, Culture, Science, Sports and Tech-
nology of Japan.
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