Kinetic Resolution of Planar-Chiral Ferrocenylphosphine Derivatives by Molybdenum-Catalyzed Asymmetric Ring-Closing Metathesis and Their Application in Asymmetric Catalysis

Article abstract of DOI:10.1021/acscatal.5b02692

Highly enantioselective kinetic resolution of racemic planar-chiral metallocenylphosphine sulfides was realized by the molybdenum-catalyzed asymmetric ring-closing metathesis reaction with the k_rel values of up to 147. The enantiomerically enriched 1,4-but-2-enylene-bridged ferrocenylphosphine sulfides thus obtained could be purified to enantiomerically pure forms by simple recrystallization from hot methanol, and subsequent reduction of the phosphine sulfides provided the corresponding planar-chiral phosphines with retention of the enantiomeric homogeneity. This is a rare example of preparing planar-chiral ferrocenylphosphines by catalytic asymmetric reactions. The single-enantiomer planar-chiral ferrocenylphosphines were applied as chiral ligands in the rhodium-catalyzed asymmetric 1,4-addition reaction (the Hayashi-Miyaura conjugate addition reaction) of phenylboronic acid to 2-cyclohexenone to show excellent enantioselectivity and high yields. The NMR studies clarified that the butenylene-bridged ferrocenylphosphine coordinated to a rhodium(I) cation in a monodentate fashion and an interaction of the bridging olefin moiety to the rhodium atom was not detected.

Full text of DOI:10.1021/acscatal.5b02692

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Article
Kinetic Resolution of Planar-Chiral Ferrocenylphosphine
Derivatives by Molybdenum-Catalyzed Asymmetric Ring-Closing
Metathesis and Their Application in Asymmetric Catalysis
Masamichi Ogasawara, Sachie Arae, Susumu Watanabe, Kiyohiko Nakajima, and Tamotsu Takahashi
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b02692 • Publication Date (Web): 15 Jan 2016
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Kinetic Resolution of Planar-Chiral
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Ferrocenylphosphine Derivatives by Molybdenum-
Catalyzed Asymmetric Ring-Closing Metathesis and
Their Application in Asymmetric Catalysis
Masamichi Ogasawara,*,† Sachie Arae,† Susumu Watanabe,† Kiyohiko Nakajima,‡ and Tamotsu
Takahashi*,†
† Institute for Catalysis and Graduate School of Life Science, Hokkaido University, Kita-ku,
Sapporo 001-0021, Japan
‡
Department of Chemistry, Aichi University of Education, Igaya, Kariya, Aichi, 448-8542,
Japan
Abstract. Highly enantioselective kinetic resolution of racemic planar-chiral
metallocenylphosphine sulfides was realized by the molybdenum-catalyzed asymmetric ring-
closing metathesis reaction with the krel values of up to 147. The enantiomerically enriched 1,4-
but-2-enylene-bridged ferrocenylphosphine sulfides thus obtained could be purified to
enantiomerically pure forms by the simple recrystallization from hot methanol, and subsequent
reduction of the phosphine sulfides provided the corresponding planar-chiral phosphines with
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retention of the enantiomeric homogeneity. This is a rare example of preparing planar-chiral
ferrocenylphosphines by catalytic asymmetric reactions. The single-enantiomeric planar-chiral
ferrocenylphosphines were applied as chiral ligands in the rhodium-catalyzed asymmetric 1,4-
addition reaction (the Hayashi-Miyaura conjugate addition reaction) of phenylboronic acid to 2-
cyclohexenone to show excellent enantioselectivity and high yields. The NMR studies clarified
that the butenylene-bridged ferrocenylphosphine coordinated to a rhodium(I) cation in a
monodentate fashion and an interaction of the bridging olefin moiety to the rhodium atom was
not detected.
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Keywords. planar-chiral; metallocene; ring-closing metathesis; enantioselective; kinetic
resolution; ferrocenylphosphine; molybdenum-alkylidene
Introduction
Chiral phosphines are arguably the most important chiral scaffolds in transition-metal-
catalyzed asymmetric reactions.1 Among various chiral phosphines reported so far, planar-chiral
ferrocenylphosphines are one of the most successful classes of chiral ligands in transition-metal
catalysis.2 Since the first introduction of a planar-chiral ferrocenylphosphine as (R)-(S)-ppfa (B
in Scheme 1) by Hayashi and Kumada in 1974,3 numerous such ferrocenylphosphines have been
developed with considerable success.2 Surprisingly, however, their synthetic methods in optically
active forms are rather limited. Standard methods of preparing enantiomerically enriched planar-
chiral ferrocenes are based on diastereoselective metalation using preinstalled chiral directing
groups4 or external chiral bases,5 and these strategies have been successfully utilized in the
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preparation of planar-chiral ferrocenylphosphines.3,6 A notable synthetic precursor to planar-
chiral ferrocenylphosphines is (R)- or (S)-N,N-dimethyl-(1-ferrocenylethyl)amine (A; Scheme 1),
which is known as "Ugi's amine".4a,b The 1-(dimethylamino)ethyl group in A is an effective
chiral directing group at the ortho-lithiation of A to induce the ferrocene-based planar-chirality
by the diastereoselective control. Trapping of the lithiated intermediate with Ph2PCl provides B
in 92% de.3a Various other planar-chiral ferrocenylphosphines, such as Josiphos7 and TRAP,8 can
be derived from A as well. Although the diastereoselective directed ortho-lithiation protocols are
highly effective for preparing planar-chiral ferrocene derivatives, these methods generally
require stoichiometric chiral sources for inducing/controlling the planar chirality. Whereas
catalytic asymmetric reactions of preparing scalemic planar-chiral ferrocenes are limited,5d,9-11
examples of catalytic asymmetric syntheses of planar-chiral ferrocenylphosphines have been
extremely rare.
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Me
Me
Li
Me
H
H
H
NMe2
NMe2
NMe2
PPh2
nBuLi
Ph2PCl
Fe
Fe
Fe
(92% de)
(R)-Ugi's amine (A)
(R)-(S)-ppfa (B)
Me
H
Ph2P
Fe
Me
H
PCy2
PPh2
Fe
Fe
PPh2
H
Me
(S,S)-(R,R)-Ph-TRAP
(R)-(S)-Josiphos
Scheme 1. Ugi's Amine (A) and Representative Planar-Chiral Ferrocene-Based Phosphine
Ligands Derived from A.
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Recently, we have developed a protocol for the enantioselective kinetic resolution of racemic
planar-chiral ferrocenes by the molybdenum-catalyzed asymmetric interannular ring-closing
metathesis (ARCM; Scheme 2).11a,b,12 Although our method is highly effective for the kinetic
resolution of certain ferrocene substrates with the krel values of up to >500, the scope of the
method described in our original reports was rather limited: (i) the substrates used were alkyl- or
silylferrocenes and functionalized substrates were not examined; (ii) only a single molybdenum-
alkylidene species was employed as a precatalyst, and effects of various other chiral ligands were
unexplored.
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tBu
tBu
tBu
tBu
tBu
(R)-Mo* cat.
krel = 186
Fe
tBu
+
Fe
Fe
(R)-product
96% ee (46%)
(S)-substrate
95% ee (47%)
rac-substrate
Scheme 2. Kinetic Resolution of Racemic Planar-Chiral Ferrocene by Molybdenum-Catalyzed
Asymmetric RCM.
In this article, we report the results of our studies on the application of the ARCM method to
the enantioselective kinetic resolution of planar-chiral ferrocenyl- and ruthenocenylphosphine
derivatives. After the extensive survey of various reaction conditions, including the screening of
the molybdenum-alkylidene precatalysts, the planar-chiral metallocenylphosphine sulfides were
obtained with excellent enantioselectivity of >90% ee. We also systematically investigated the
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correlation between the structural motifs in the metallocene substrates and the enantioselectivity
of the reactions to clarify the structural requirements of the substrates for the high
enantioselectivity. The enantiomerically enriched ferrocene products could be purified into
enantiomerically pure forms by the simple recrystallization, and subsequent their reduction
afforded the corresponding ferrocenylphosphines. The obtained single-enantiomeric
ferrocenylphosphines were applied in a couple of transition-metal-catalyzed asymmetric
reactions as chiral ligands and found to be highly effective in the rhodium-catalyzed asymmetric
1,4-addition reaction (the Hayashi-Miyaura conjugate addition reaction)13 of phenylboronic acid
to 2-cyclohexenone. It should be emphasized that this is a rare example of catalytic asymmetric
synthesis of planar-chiral ferrocenylphosphines and the phosphines obtained herewith are indeed
functioning as effective chiral ligands in asymmetric catalysis.
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Results and Discussion
Design and Preparation of Metallocenylphosphine Substrates for ARCM Kinetic
Resolution. Our preliminary studies on the kinetic resolution of the racemic planar-chiral
alkylferrocenes postulated that a couple of structural factors in the substrates were crucial to
achieve the high enantioselectivity in the molybdenum-catalyzed ARCM: (i) steric
discrimination of the two allylic groups with a methyl substituent at the 2-allylic position of one
of the two allylic groups, and (ii) a bulky substituents at the position adjacent to the unsubstituted
(i.e., the more reactive) allyl group (Figure 1).11a,b We assumed that an Ar2P(=E)- group might
work as a proper bulky substituent required in the effective ARCM kinetic resolution. And thus,
metallocenes 1 were designed as potential "good" substrates for the present kinetic resolution
study. In addition to 1a-g that fulfill the two structural requirements mentioned above, 1h and 1i
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were also prepared for comparison although these two were expected to be "poor" substrates for
the kinetic resolution reaction (see, Schemes 3 and 4).
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a bulky substituent adjacent to
the more reactive allyl group
E
tBu
tBu
PAr2
Fe
M
differentiating two allylic groups
Me
1
M = Fe, Ru
Ar = aryl
E = none, O, S, Se
Figure 1. Design of planar-chiral ferrocenylphosphine derivatives as substrates for
molybdenum-catalyzed ARCM kinetic resolution.
Preparation of 1a-h was achieved by the regioselective and stepwise introduction of the three
substituents starting with 1,1'-dibromoferrocene/ruthenocene14 as outlined in Scheme 3. First, a
diarylphosphino group [aryl = Ph, -C6H3-3,5-Me2 (Xyl), -C6H2-3,5-tBu2-4-OMe (DTBM)] was
introduced to the dibromometallocene core by regioselective ortho-lithiation using lithium
tetramethylpiperidide15 followed by quenching the lithiated species with diarylchlorophosphine,
and subsequent oxidation with H2O2 gave 3 in 79-91% yields. The lithium-bromine exchange on
3 using one equivalent of butyllithium took place at the bromide adjacent to the diarylphosphinyl
group selectively, probably the Lewis basic phosphinyl group worked as a directing group, and a
following reaction with allyl bromide in the presence of CuCl gave 4 in 71-86% yields. The
remaining bromide in 4 was replaced with methallyl (or allyl) group in the same way. The
obtained phosphine oxides were reduced to the corresponding phosphines with
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trichlorosilane/triethylamine and subsequently derivatized to phosphine chalcogenides as needed
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to furnish desired substrates 1a-h selectively.
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O
O
PAr2
PAr2
1) LiTMP
1) nBuLi
M
Br
Br
M
Br
Br
M
2) CuCl, DMPU,
allyl-Br
2) Ar2PCl
3) H2O2
Br
rac-3 (79-91%)
rac-4 (71-86%)
O
E
PAr2
PAr2
1) nBuLi
1) HSiCl3, NEt3
2) chalcogen
M
M
2) CuCl, DMPU,
methallyl-Br
or allyl-Br
R
rac-1a
R
rac-1b-h
(82-91%)
(70-83%)
a: M = Fe, R = Me, Ar = Ph, E = O
b: M = Fe, R = Me, Ar = Ph, E = none
c: M = Fe, R = Me, Ar = Ph, E = S
d: M = Fe, R = Me, Ar = Ph, E = Se
e: M = Fe, R = Me, Ar = C6H3-3,5-Me2 (Xyl), E = S
f: M = Fe, R = Me, Ar = C6H2-3,5-tBu2-4-OMe (DTBM), E = S
g: M = Ru, R = Me, Ar = Ph, E = S
h: M = Fe, R = H, Ar = Ph, E = S
Scheme 3. Preparation of ARCM Kinetic Resolution Substrates rac-1a-h.
On the other hand, substrate 1i was prepared by an unstylish manner (Scheme 4). A reaction
of FeCl2 with a mixture of Na+(methallyl-C5H4)– and Li+[1,2- and 1,3-allyl(Ph2P)C5H3]– followed
by a treatment with S8 afforded a mixture of several ferrocene derivatives, of which careful
chromatographic separation provided pure rac-1i albeit in low yield (31%).
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S
PPh2
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Fe
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1) Ph2PCl
2) nBuLi
rac-1i
(31%)
–
–
• Li+
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• Na+
PPh2
1)FeCl2
2) S8
+
S
PPh2
Fe
S
–
• Na+
Ph2P
meso- & rac-/
1,2- & 1,3-isomers
+ rac-1c
+ (methallyl-C5H4)2Fe
Scheme 4. Preparation of Substrate rac-1i.
Molybdenum-Catalyzed ARCM Kinetic Resolution of Racemic Planar-Chiral
Ferrocenylphosphine Derivatives 1. The prepared substrates 1 were subjected to the kinetic
resolution studies under various conditions in the presence of a molybdenum-alkylidene
precatalyst which was generated in situ from the molybdenum precursor
[(pyrrolyl)2Mo(=CHCMe2Ph)(=NC6H3-2,6-iPr2)] and an appropriate axially chiral binaphthol
derivative as reported by Hoveyda and Schrock.16 At the outset, a proper choice of the P=E
moieties in rac-1 was determined for substrates rac-1a-d (Table 1; entries 1-4). The RCM
reactions were carried out in benzene at 60 °C in the presence of the Mo-alkylidene precatalyst
(10 mol %) generated with (R)-L1.16,17a Under these conditions, phosphine oxide rac-1a was inert
and desired cyclized species 2a was not obtained at all (entry 1). On the other hand, phosphine
rac-1b and phosphine sulfide rac-1c afforded the corresponding cyclized products 2b (6%) and
2c (17%), respectively, but their yields were far from satisfactory (entries 2 and 3). It was
rationalized that Lewis basic 1a and 1b poisoned the Lewis acidic molybdenum-alkylidene
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species. Phosphine selenide rac-1d was unstable under the RCM conditions, and the reaction of
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4).
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Next, screening of chiral biaryloxide ligands in the molybdenum catalysts was examined for
the ARCM reactions of rac-1c. Most of the chiral ligands examined, (R)-L1-3,17a-c were found to
be inactive or nearly inactive (Table 1; entries 3, 5 and 6), however, the Mo-alkylidene species
generated with (R)-L417d showed reasonable catalytic activity and enantioselectivity to give
cyclized (S)-2c in 62% yield and 53% ee together with recovered (R)-1c of 97%ee in 31% yield
(entry 7). The krel value ([rate of fast-reacting enantiomer]/[rate of slow-reacting enantiomer];
selectivity factor) for this reaction is estimated to be 13.18 Lowering the temperature improved
the selectivity; the reaction at 23 °C showed excellent enantioselectivity with the krel value of 65
giving (S)-2c of 88% ee in 52% yield and (R)-1c of 97% ee in 43% yield (entry 8).
Table 1. Molybdenum-Catalyzed ARCM Kinetic Resolution of Planar-Chiral
Metallocenylphosphine Derivatives: Optimization of Reaction Conditionsa
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E
PPh2
Mo/(R)-L cat.
(10 mol %)
E
E
Fe
Fe
Fe
+
Ph2P
PPh2
C6H6
60 °C, 24 h
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(S)-2a-d
(R)-1a-d
rac-1a-d
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R'
R'
iPr
R'
OH
OH
OH
OH
iPr
Me Mo
Ph
N
O
O
R'
R'
R'
Me
(R)-L1: R' = tBu
(R)-L2: R' = C6H3-3,5-(CF3)2
(R)-L3: R' = C6H2-2,4,6-iPr3
Mo/(R)-L cat.
(R)-L4: R' = CHPh2
e
entry
substrate
rac-1a
rac-1b
rac-1c
rac-1d
rac-1c
rac-1c
rac-1c
rac-1c
chiral L
(R)-L1
(R)-L1
cyclized 2b,d
–– (0%)
recovered 1c,d
krel
1
2
3
4
5
6
7
8f
–– (>90%)
––
7.0
15
––
––
––
13
65
75% ee (6%)
5% ee (88%)
(R)-L1
(R)-L1
(R)-L2
(R)-L3
(R)-L4
(R)-L4
85% ee (17%) 21% ee (76%)
messy
–– (0%)
–– (>90%)
n.d. (90%)
<1% ee (8%)
53% ee (62%) 97% ee (31%)
88% ee (52%) 97% ee (43%)
a The reaction was carried out using 1 ( 0.16 mmol) in benzene at 60 °C for 24 h in the
presence of an appropriate metathesis catalyst generated in situ (10 mol %) unless otherwise
noted. b Enantiomeric excess was determined by chiral HPLC (see Supporting Information for
detail). c Enantiomeric excess of recovered 1 was determined after conversion into 2 by a
reaction with the Grubbs-II catalyst. d Isolated yield in parentheses. e Calculated based on a first-
order equation (ref. 18). f At 23 °C.
After the optimization studies, Mo/(R)-L4 precatalyst was applied to the other phosphine
sulfide substrates (Table 2). The substrate rac-1e, which has a bis(3,5-xylyl)thiophosphinyl
substituent in place of the Ph2P(=S)- group in 1a, was also resolved as above. The
enantioselectivity and the reaction efficiency of kinetic resolution of rac-1e was still high with
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the krel value of 62 (entry 2). With a much bulkier thiophosphinyl group in rac-1f, the ARCM
reaction needed to be conducted at higher temperature (40 °C). However, the selectivity was still
excellent with krel = 43 (entry 3). The reaction of ruthenocenylphosphine sulfide rac-1g was also
conducted at 40 °C to show the highest selectivity with the krel factor of 147, and the ARCM
product (2g) and the recovered substrate (1g) were obtained in 96% ee and 89% ee, respectively
(entry 4). Enantioselectivity of the ARCM kinetic resolution was strongly dependent on the
structures of the allylic groups in the substrates. Introduction of C5H4-allyl in place of C5H4-
methallyl in rac-1h diminishes enantioselectivity of the asymmetric reaction. With two
unsubstituted allyl groups in it, the RCM of rac-1h was very rapid and completed within an hour.
For this reason, the kinetic resolution of rac-1h was conducted at 23 °C for 5 min with lower
catalyst loading. The reaction with Mo/(R)-L4 afforded cyclized product 2h in 16% ee and
recovered 1h in 7% ee. The selectivity factor for the reaction is only 1.5 (entry 5). The relative
orientation between the diarylthiophosphiyl group and the allyl substituent in 1 is also crucial for
the high enantioselectivity of the kinetic resolution process (vide infra). While rac-1c showed the
excellent selectivity (entry 1), the ARCM reaction of rac-1i, that is with a 1,3-substituted
cyclopentadienide, was much less selective with the krel value of less than 1.1 (entry 6).
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40
41
42
43
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Molybdenum-Catalyzed ARCM Kinetic Resolution of Planar-Chiral
Metallocenylphosphine Sulfidesa
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S
PAr2
Mo/(R)-L4 cat.
(10 mol %)
S
S
M
Ar2P
M
M
+
PAr2
C6H6, 24 h
7
8
9
R
(S)-2c,e-h
(R)-1c,e-h
rac-1c,e-h
R
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R
S
S
PPh2
Ph2P
Mo/(R)-L4 cat.
(10 mol %)
S
Fe
Fe
Fe
+
Ph2P
C6H6, 15 min
(–)-2i
(+)-1i
rac-1i
absolute configuraion not determined.
e
entry
1f
substrate
temp.
cyclized 2b,d
recovered 1c,d
krel
rac-1c
rac-1e
rac-1f
rac-1g
rac-1h
rac-1i
23 °C
23 °C
40 °C
40 °C
23 °C
23 °C
88% ee (52%) 97% ee (43%)
90% ee (53%) 92% ee (45%)
89% ee (48%) 81% ee (47%)
96% ee (48%) 89% ee (49%)
65
62
2
3
43
4
147
1.5
<1.1
5g
16% ee (29%)
7% ee (64%)
6h
3% ee (30%)
1% ee (49%)
a The reaction was carried out using 1 ( 0.16 mmol) in benzene for 24 h in the presence of
Mo/(R)-L4 precatalyst generated in situ (10 mol %) unless otherwise noted. b Enantiomeric
excess was determined by chiral HPLC (see Supporting Information for detail). c Enantiomeric
excess of recovered 1 was determined after conversion into 2 by a reaction with the Grubbs-II
catalyst. d Isolated yield in parentheses. e Calculated based on a first-order equation (ref. 18). f
Same with entry 8 in Table 1. g With 5 mol % catalyst loading for 5 min. h For 15 min.
Determination of Absolute Configuration of (–)-2e. Single crystals of (–)-2e suitable for X-
ray crystallography were grown from the hot methanol solution as orange prisms. The crystal
structure of (–)-2e is shown in Figure 2 with the selected bond lengths and angles (see the
Supporting Information for details), which revealed that the absolute configuration of
22
levorotatory 2e ([α]D = –1.75 (c = 1.76, CHCl3) for the sample of 94% ee) was (S). The
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configurations of the other ARCM kinetic resolution products were deduced by analogy. The
iron atom in 2e located at the center of the two η5-ligands: the distance from Fe(1) to the least-
squares planes of η5-C(6-10) and η5-C(11-15) are 1.636(9) Å and 1.642(9) Å, respectively. The
two η5-ligands are slightly tilted due to the bridging moiety and the dihedral angle between the
two η5-C5 planes is 6.06(10)°, which is within the range of those found in the analogous
[4]ferrocenophanes.11a-c,19
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Figure 2. Ball-and-stick drawing of (S)-(–)-2e. All hydrogen atoms are omitted for clarity.
Selected bond lengths (Å) and angles (deg): C(6)-C(1) = 1.52(1), C(1)-C(2) = 1.50(1), C(2)-C(3)
= 1.33(1), C(3)-C(4) = 1.51(1), C(4)-C(11) = 1.49(1), Fe(1)-least-squares planeC(6-10) = 1.636(9),
Fe(1)-least-squares planeC(11-15) = 1.642(9); dihedral angle between the two Cp planes = 6.06(10).
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Consideration of Stereochemical Pathways of Molybdenum-Catalyzed ARCM Kinetic
Resolution of 1. Plausible reaction pathways of the Mo-catalyzed ARCM kinetic resolution of
rac-1c are illustrated in Scheme 5. Whereas a less substituted olefin is more reactive than a more
substituted one in olefin metathesis, the initial reactions between Mo/(R)-L4 and (S)- or (R)-1c
take place at the parent allyl group to form intermediates C or D, respectively, and the formation
of intermediate F is unlikely. The methallylic olefin in C is able to take a position proximal to
the molybdenum center, and thus C gives (S)-2c smoothly by the intramolecular second
metathesis. On the other hand, epimeric D is forced to take non-productive conformation in E
due to the steric repulsion between the diphenylthiophosphinyl substituent in the ferrocene
moiety and the diphenylmethyl group in the chiral biaryloxide ligand. Subsequent intermolecular
metathesis between E and (S)-1c liberates (R)-1c intact together with intermediate C.
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R' = -CHPh2
Ar
R'
P = -P(=S)Ph2
N
O
O
Mo
8
9
R'
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11
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Fe
P
F
+ rac-1c
unfavored
iPr
R'
+ (S)-1c
– CH2=CHCMe2Ph
+ (R)-1c
– CH2=CHCMe2Ph
iPr
Me Mo
Ph
N
O
O
R'
Me
Mo/(R)-L4 cat.
Ar
R'
N
Ar
R'
N
O
O
Mo
O
O
Mo
R'
P
R'
Fe
D
C
Fe
+ (S)-1c
P
Ar
R'
– [Mo/(R)-L4]
N
O
O
Mo
P
R'
Fe
P
Fe
P
Fe
(R)-1c
(S)-2c
E
Scheme 5. Plausible Stereochemical Pathways of ARCM Kinetic Resolution of rac-1c Catalyzed
by Mo/(R)-L4.
While rac-1c and rac-1e-g were resolved efficiently in the same way by the Mo-catalyzed
ARCM, the kinetic resolution of rac-1h and rac-1i were much less selective (see Table 2).
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9
Substrate rac-1h possesses two parent allyl groups instead of the allyl/methallyl combination in
rac-1c, and thus the RCM reaction of rac-1h may be initiated at both allyl substituents. That is,
two intermediates G and H are involved in the ARCM of rac-1h. Intermediate G is favored over
H, because G is sterically less congested. Whereas the C5H4-bound allyl group in rac-1h is
remote from the planar-chiral environment regulated by η5-C5H3(P(=S)Ph2)(allyl), the formation
of diastereomeric G is less selective. Following ring-closure step, which is an intramolecular
process, proceeds smoothly in both (Ra,Rp)- and (Ra,Sp)-G to give 2h with the low
enantioselectivity (Scheme 6, top).
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On the other hand, the low enantioselectivity in the kinetic resolution of rac-1i, which is with
a 1,3-substituted cyclopentadienide, can be rationalized as lack of the crucial steric interaction in
intermediate I. Since the thiophosphinyl group in I is remote from the chiral Mo[(R)-biaryloxide]
core, no effective diastereomeric interaction is operated in I (cf., the steric interaction in D)
leading to the low enantioselectivity of the kinetic resolution process (Scheme 6, bottom).
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Ar
R'
N
O
O
Mo
8
9
R'
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Fe
P
(Ra,Rp)- &
(Ra,Sp)-G
rac-1h
+
Mo/(R)-L4
(R)- & (S)-2h
(low ee)
Ar
R'
N
O
O
Mo
R'
Fe
(Ra,Rp)- &
(Ra,Sp)-H
P
R' = -CHPh2
P = -P(=S)Ph2
Ar
R'
N
O
O
rac-1i
+
Mo/(R)-L4
Mo
(R)- & (S)-2i
(low ee)
R'
Fe
(Ra,Rp)- &
(Ra,Sp)-I
P
Scheme 6. Plausible Pathways of ARCM Kinetic Resolution of rac-1h and rac-1i Catalyzed by
Mo/(R)-L4.
Preparation of Enantiomerically Pure Planar-Chiral Ferrocenylphosphines 5 and
Hydrogenated Derivative 7. Enantiomerically enriched planar-chiral ferrocenylphosphine
sulfides (R)- or (S)-2c, 2e, and 2f obtained by the Mo-catalyzed kinetic resolution could be
further purified by recrystallization from hot methanol to give the respective planar-chiral
compounds in essentially enantiomerically pure form (>99.8% ee). Reduction of single-
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enantiomeric phosphine sulfides 2 was achieved by treating with excess P(NMe2)3 to give the
corresponding ferrocenylphosphines 5 quantitatively.20-22 The enantiopurity of the phosphine
sulfides was retained during the reduction, and phosphines 5 were also single-enantiomeric
(Scheme 7).
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Dextrorotatory (R)-2e was hydrogenated under 1 atom of H2 in the presence of the modified
Crabtree's catalyst, [Ir(cod)(PCy3)(py)]BArF to give a diastereomeric mixture of (Rc,Rp)- and
23
4,
(Sc,Rp)-6e in a 94/6 ratio. The minor diastereomer was removed by HPLC purification, and
purified (Rc,Rp)-6e was reduced as above to give the corresponding ferrocenylphosphine (Rc,Rp)-
7e as a single stereoisomer (Scheme 7).
S
S
PAr2
PAr2
PAr2
P(NMe2)3
(20 equiv.)
recrystn
from MeOH
Fe
Fe
Fe
toluene
110 °C, 20 h
(95-97%)
(S)- or (R)-5c,†e,f
(S)- or (R)-2c,e,f
(S)- or (R)-2c,e,f
(>99.8% ee)
(88-97% ee)
(>99.8% ee)
(R)-2e (Ar = C6H3-3,5-Me2; Xyl)
[Ir(cod)(PCy3)(py)]BArF4 (10 mol %)
H2 (1 atm), CH2Cl2, 24 h
(60%)
then purified by HPLC
S
PXyl2 P(NMe )
PXyl2
2 3
(20 equiv.)
Fe
Fe
toluene
110 °C, 20 h
(97%)
H
Me
H
Me
†5c = 2b
(R,R)-6e
(R,R)-7e
(>99.8% ee)
(>99.8% ee)
Scheme 7. Preparation of Enantiomerically Pure Planar-Chiral Ferrocenylphosphines 5c, e, f,
and 7e.
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Application of Planar-Chiral Ferrocenylphosphines 5 and 7 to Rh- and Pd-Catalyzed
Asymmetric Reactions. The synthetic utility of the planar-chiral ferrocenylphosphines as chiral
ligands was examined in two transition-metal-catalyzed asymmetric reactions. The first one is
the rhodium-catalyzed asymmetric 1,4-addition reaction (the Hayashi-Miyaura conjugate
addition reaction) of phenylboronic acid to 2-cyclohexenone (Table 3).13,24 A rhodium catalyst
generated in situ from Rh(acac)(C2H4)2 and (R)-5c (2 equiv. to Rh) showed excellent
performance in the reaction and (S)-3-phenylcyclohexanone was obtained in 94% ee and 89%
yield (entry 1). Phosphine (R)-5e was as effective as (R)-5c in the Rh-catalyzed reaction giving
the desired product in 94% ee (entry 2). A catalyst generated from an equimolar mixture of
Rh(acac)(C2H4)2 and (R)-5e retained the high catalytic activity as well as the high
enantioselectivity as above (entry 3). On the other hand, phosphine (R)-5f, which is with a bulky
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bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino
group,
showed
slightly
lower
enantioselectivity (entry 4). Ligand (R)-7e possesses a saturated bridging tether but is otherwise
isostructural to (R)-5e. Indeed, the effect of the saturated bridging tether is minimal and the
rhodium species coordinated with (R)-7e showed nearly identical activity and selectivity with
those of the Rh/(R)-5e species (entries 2 and 5).
Table 3. Rhodium-Catalyzed Asymmetric 1,4-Addition of Phenylboronic Acid to 2-
Cyclohexenonea
O
O
Rh(acac)(C2H4)2 (3 mol %)
phosphine 5 or 7e
+ PhB(OH)2
(5.0 equiv)
dioxane/ H2O = 5/ 1
100 °C, 12 h
Ph
entry
chiral ligand
ligand/Rh
yield (%)b
% eec
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1
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5
(R)-5c
(R)-5e
(S)-5e
(R)-5f
(R)-7e
2
2
1
2
2
89
99
93
89
88
94 (S)
94 (S)
95(R)
87 (S)
94 (S)
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a The reaction was carried out using 2-cyclohexenone (0.156 mmol) in dioxane/H2O (5/1) in
the presence of the rhodium catalyst (3 mol %) generated in situ from Rh(acac)(C2H4)2 and the
chiral ligand. b Isolated yield by silica gel chromatography. c Determined by chiral HPLC
analysis.
The second reaction examined was the palladium-catalyzed asymmetric hydrosilylation,25 and
the applicability of (R)-5c and (R)-5e was explored for the reaction between styrene and
trichlorosilane (Scheme 8). A palladium complex generated in situ from [PdCl(π-allyl)]2 and the
equimolar ferrocenylphosphine ligand catalyzed the reaction smoothly to provide the desired
hydrosilylation product, whose yield and enantiomeric purity were determined after converting it
into 1-phenylethanol by the Tamao-Flemming oxidation.26 In both cases, the enantioselectivity
was moderate with around 30% ee, however, these results clearly indicate that the applications of
the ferrocenylphosphine ligands 5 are not limited to the Rh(I)-catalyzed reaction, and the ligands
might be applicable to various transition-metal-catalyzed asymmetric reactions.
[PdCl(!-allyl)]2 (0.05 mol %)
phosphine (R)-5 (0.1 mol %)
SiCl3
OH
HSiCl3
(neat)
+
Ph
23 °C, 12 h
Ph
Ph
H2O2, KF, KHCO3
THF/MeOH
0 °C, 3 h
with (R)-5c: (S)-31% ee (90%)
with (R)-5e: (S)-26% ee (92%)
Scheme 8. Palladium-Catalyzed Asymmetric Hydrosilylation of Styrene with Trichlorosilane.
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8
Coordination mode of ferrocenylphosphines 5 to Rh(I). We recently disclosed that planar-
chiral (π-arene)chromium-based phosphine J was an exceptionally effective chiral ligand in
various transition-metal-catalyzed asymmetric reactions.27 Phosphine J coordinates to a Rh(I)
cation in a bidentate fashion with the phosphine and the olefin donors, and the chelate
coordination plays an important role for the high enantioselectivity (Scheme 9).24 Whereas
ferrocenylphosphines 5 possess a phosphine/olefin substructure somewhat similar to that in J,
initially its coordination to a Rh(I) cation was postulated to be bidentate as in the case with J.
However, the results of the Rh-catalyzed 1,4-addition reaction summarized in Table 3 indicated
that ferrocenylphosphines 5 might behave as monodentate ligands upon the coordination to a
Rh(I) cation since 7e, which has no olefin substructure in it, showed nearly identical catalytic
activity and enantioselectivity with those of 5e (Table 3, entries 2 and 5). These are clear contrast
to the difference between J and K in the Rh-catalyzed reaction. Ligand K possesses the saturated
bridging tether but is otherwise isostructural to J. Due to the absence of an olefinic donor moiety,
K is unable to coordinate to a Rh(I) atom in the bidentate fashion. The outcome of this structural
change is drastic and the rhodium species coordinated with K showed virtually no
enantioselectivity in the Rh-catalyzed 1,4-addition reaction giving a nearly racemic product.
9
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Cl
Rh
Ph2P
PPh2
Cr
1/2 [RhCl(cod)]2
1/2
Me
Cr
CO
CO
CO
CO
P
Me
P
Ph2
Ph2
(R)-J
Ph2P
2
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Me
Cr
H
CO
CO
1) BH3•THF
2) CH3CH2CO2H
P
Ph2
(R,R)-K
[RhCl(C2H4)2]2
(2.5 mol %)
Chiral Ligand
(5.2 mol %)
O
O
+ p-MeOC6H4B(OH)2
KOH (0.5 eq)
dioxane/H2O (10/1)
50 °C, 9 h
(3.0 equiv)
p-C6H4OMe
with (R)-J: 98% ee (99%)
with (R,R)-K: <1% ee (27%)
Scheme 9. (π-Arene)chromium-Based Planar-Chiral Phosphine Ligands and Their Application
in the Rh-Catalyzed 1,4-Addition of p-MeOC6H4B(OH)2 to Cyclohexenone.27b
With the above-mentioned considerations in mind, the coordination mode of 5c to a Rh(I)
cation was examined by the NMR experiments. A reaction of (R)-5c (31P-NMR: δ –20.9) and a
half equivalent of [RhCl(cod)]2 in C6D6 at room temperature afforded a new rhodium species 8
quantitatively in the time of mixing (Figure 3, top). Upon the coordination to the Rh(I) cation,
31
the P-NMR resonance for the free phosphine in (R)-5c was shifted downfield to δ 18.3 in 8
with the large P-Rh coupling (JP-Rh = 147.3 Hz), which indicated the direct ligation at the Ph2P-
(η5-C5) moiety to the rhodium atom. In the H-NMR spectra, the olefinic H atom in (R)-5c was
1
detected at δ 5.66, which was slightly shifted downfield to δ 5.92 upon the coordination to Rh(I)
in 8 (Figure 3, bottom). This chemical shift is within the normal range for free olefinic hydrogens.
All these NMR observations clearly indicate that ferrocenylphosphine (R)-5c behaves as a simple
monodentate phosphine, not as a P-olefin bidentate ligand, in 8. In accordance with these, the
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signals assignable for the η2-coordinating cyclooctadiene were detected in the 1H-NMR spectrum
of 8: δ 5.84 (br, free -CH=CH-, 2H), 3.06 (br, Rh-η2-CH=CH, 1H), 2.86 (br, Rh-η2-CH=CH, 1H).
The MS measurement revealed complex 8 to be dimeric, and the structure with the two µ-Cl
ligands is proposed as shown in Figure 3.
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b
b
PPh2
g/h
h/g
Cl
Rh
PPh2
Fe
d
1/2
(R)-5c
c,f
a
+
Fe
1/2 [RhCl(cod)]2
2
e,i
8
Cp
d
i
b
e
a
f
g
h
c
Figure 3. Formation of complex 8 and its 1H-NMR spectrum in the olefinic/Cp/allylic region at
400 MHz in C6D6.
Conclusions
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Highly enantioselective kinetic resolution of racemic planar-chiral metallocenylphosphine
sulfides was realized by the molybdenum-catalyzed asymmetric ring-closing metathesis reaction.
Recrystallization of the obtained enantiomerically enriched 1,4-but-2-enylene-bridged
ferrocenylphosphine sulfides afforded the single-enantiomeric products, and subsequent their
reduction provided the corresponding ferrocenylphosphines. Whereas no racemization was
associated with the reduction process, the ferrocenylphosphines thus obtained were also single-
enatiomeric. The enantiomerically pure planar-chiral ferrocenylphosphines were applied as chiral
ligands in the rhodium-catalyzed asymmetric 1,4-addition reaction of phenylboronic acid to 2-
cyclohexenone to show excellent enantioselectivity and high yields. The NMR studies clarified
that the butenylene-bridged ferrocenylphosphine coordinated to a rhodium(I) cation in a
monodentate fashion and an interaction of the bridging olefin moiety to the rhodium atom was
not detected.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures, compound characterization data, and
crystallographic data of ferrocenylphosphine sulfide (S)-(–)-2e (CIF file). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
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ogasawar@cat.hokudai.ac.jp
tamotsu@cat.hokudai.ac.jp
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ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid for Scientific Research (B) (15H03805) to M.O.
from MEXT, Japan. S.A. and S.W. were recipients of the JSPS Research Fellowship for the
Young Scientists.
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