Kinetic resolution of planar-chiral ferrocenes by molybdenum-catalyzed enantioselective metathesis

Article abstract of DOI:10.1021/om0608298

Kinetic resolution of planar-chiral I.1'-diallylferrocene derivatives was realized by molybdenum-catalyzed asymmetric ring-closing metathesis with excellent enantioselectivity. This is the first example of highly enantioselective metal-catalyzed methods o

Full text of DOI:10.1021/om0608298

Organometallics 2006, 25, 5201-5203
5201
Communications
Kinetic Resolution of Planar-Chiral Ferrocenes by
Molybdenum-Catalyzed Enantioselective Metathesis
Masamichi Ogasawara,*,† Susumu Watanabe,† Liyan Fan,† Kiyohiko Nakajima,‡ and
Tamotsu Takahashi*,†
Catalysis Research Center and Graduate School of Pharmaceutical Sciences, Hokkaido UniVersity, and
SORST, Japan Science and Technology Agency (JST), Kita-ku, Sapporo 001-0021, Japan, and Department
of Chemistry, Aichi UniVersity of Education, Igaya, Kariya, Aichi, 448-8542, Japan
ReceiVed September 11, 2006
Scheme 1. ARCM Kinetic Resolution of Planar-Chiral
Ferrocenes and Metathesis Catalysts.
Summary: Kinetic resolution of planar-chiral 1,1′-diallylfer-
rocene deriVatiVes was realized by molybdenum-catalyzed
asymmetric ring-closing metathesis with excellent enantiose-
lectiVity. This is the first example of highly enantioselectiVe
metal-catalyzed methods of preparing optically actiVe planar-
chiral metallocenes.
Planar-chiral ferrocenes are important chiral scaffolds in
organic and organometallic chemistry.1 Although such fer-
rocenes have been used in a variety of asymmetric reactions as
ligands2 or catalysts,3 their preparation in optically active form
is still a challenging problem. Most nonracemic planar-chiral
ferrocenes were obtained either by diastereoselective metalation
utilizing chiral ortho-directing groups4 or by optical resolution
of racemic compounds. Enantioselective lithiation of prochiral
ferrocenes by a stoichiometric chiral base has also shown fair
success.5 On the other hand, examples of catalytic asymmetric
synthesis of planar-chiral ferrocene derivatives are extremely
* To whom correspondence should be addressed. E-mail:
ogasawar@cat.hokudai.ac.jp.
† Hokkaido University.
‡ Aichi University of Education.
(1) For reviews of planar-chiral ferrocenes, see: (a) Wagner, G.;
Herrmann, R. In Ferrocenes; Togni, A., Hayashi, T., Eds.; VCH: Weinheim,
1995; Chapter 4, p 173. (b) Togni, A. Angew. Chem., Int. Ed. Engl. 1996,
35, 1475. (c) Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry 1998,
9, 2377. See, also: (d) Halterman, R. L. Chem. ReV. 1992, 92, 965.
(2) (a) Hayashi, T. In Ferrocenes; Togni, A., Hayashi, T., Eds.; VCH:
Weinheim, 1995; Chapter 2, p 105. (b) Togni, A. In Metallocenes; Togni,
A., Halterman, R. L., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 2, Chapter
11, p 685. (c) Colacot, T. J. Chem. ReV. 2003, 103, 3101. (d) Barbaro, P.;
Bianchini, C.; Giambastiani, G.; Parisel, S. L. Coord. Chem. ReV. 2004,
248, 2131.
rare.6-8 Apart from several reports on enzymatic resolution of
racemic ferrocenes,6 to the best of our knowledge, only two
examples of catalytic induction of ferrocenyl planar chirality
was reported so far with modest enantioselectivity.7,8
Richards9 and we10 recently reported preparation of [4]-
ferrocenophanes by Ru- or Mo-catalyzed metathesis reaction
of 1,1′-diallylferrocenes.11 Here, we report kinetic resolution
of planar-chiral 1,1′-diallylferrocene derivatives by Mo-catalyzed
asymmetric ring-closing metathesis (ARCM).12 The reaction
(3) (a) Butsugan, Y.; Araki, S.; Watanabe, M. In Ferrocenes; Togni,
A., Hayashi, T., Eds.; VCH: Weinheim, 1995; Chapter 3, p 143. (b) Fu,
G. C. Acc. Chem. Res. 2000, 33, 412. (c) Fu, G. C. Acc. Chem. Res. 2004,
37, 542.
(4) (a) Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I.
J. Am. Chem. Soc. 1970, 92, 5389. (b) Riant, O.; Samuel, O.; Kagan, H. B.
J. Am. Chem. Soc. 1993, 115, 5835. (c) Rebiere, F.; Riant, O.; Ricard, L;
Kagan, H. B. Angew. Chem., Int. Ed. Engl. 1993, 32, 568. (d) Richards, C.
J.; Damalidis, T.; Hibbs, D. E.; Hursthouse, M. B. Synlett 1995, 74. (e)
Sammakia, T.; Latham, H. A.; Schaad, D. R. J. Org. Chem. 1995, 60, 10.
(f) Nishibayashi, Y.; Arikawa, Y.; Ohe, K.; Uemura, S. J. Org. Chem. 1996,
61, 1172. (g) Enders, D.; Peters, R.; Lochtman, R.; Raabe, G. Angew. Chem.,
Int. Ed. 1999, 38, 2421.
(5) (a) Tsukazaki, M.; Tinkl, M.; Roglans, A.; Chapell, B. J.; Taylor, N.
J.; Snieckus, V. J. Am. Chem. Soc. 1996, 118, 685. (b) Nishibayashi, Y.;
Arikawa, Y.; Ohe, K.; Uemura, S. J. Org. Chem. 1996, 61, 1172. (c) Laufer,
R. S.; Veith, U.; Taylor, N. J.; Snieckus, V. Org. Lett. 2000, 2, 629. (d)
Fukuda, T.; Imazato, K.; Iwao, M. Tetrahedron Lett. 2003, 44, 7503. (e)
Metallinos, C.; Szillat, H.; Taylor, N. J.; Snieckus, V. AdV. Synth. Catal.
2003, 345, 370.
(6) For representative examples, see: (a) Izumi, T.; Hino, T. J. Chem.
Technol. Biotechnol. 1992, 55, 325. (b) Lambusta, D.; Nicolosi, G.; Patti,
A.; Piattelli, M. Tetrahedron Lett. 1996, 37, 127. (c) Patti, A.; Lambusta,
D.; Piattelli, M.; Nocolosi, G. Tetrahedron: Asymmetry 1998, 9, 3073.
(7) Siegel, S.; Schmalz, H.-G. Angew. Chem., Int. Ed. Engl. 1997, 36,
2456.
(8) Enantioselective lithiation of prochiral ferrocenes using alkyllithium
in conjunction with substoichiometric quantities of chiral diamines was
reported recently; see: Genet, C.; Canipa, S. J.; O’Brien, P.; Taylor, S. J.
Am. Chem. Soc. 2006, 128, 9337.
(9) Locke, A. J.; Jones, C.; Richards, C. J. J. Organomet. Chem. 2001,
637-639, 669.
(10) (a) Ogasawara, M.; Nagano, T.; Hayashi, T. J. Am. Chem. Soc. 2002,
124, 9068; J. Am. Chem. Soc. 2002, 124, 12626. (b) Ogasawara, M.; Nagano,
T.; Hayashi, T. Organometallics 2003, 22, 1174.
10.1021/om0608298 CCC: $33.50 © 2006 American Chemical Society
Publication on Web 09/26/2006

5202 Organometallics, Vol. 25, No. 22, 2006
Communications
Table 1. Molybdenum-Catalyzed Asymmetric RCM Kinetic Resolution of Planar-Chiral Ferrocenesa
e
entry
substrate 1 (mol/L)b
Mo* cat. (%)
conditions
yields (%)c 2/1/3
% ee 2/1d
krel
1
2
3
4
5
6
7
8
1a (0.1)
1b (0.1)
5
5
10
5
23 °C, 15 min
23 °C, 1 h
80 °C, 24 h
70 °C, 24 h
23 °C, 4 h
50 °C, 24 h
50 °C, 24 h
50 °C, 24 h
73/26/trace
44/49/trace
26/53/16
0/54/38
23/30/47
46/47/3
<1/2
1.03
1.4
6.4
12/9
1c (0.01)
1d (0.01)
1e (0.1)
1e (0.005)
1f (0.005)
1g (0.005)
66/29
-/7
>99.5/78
96/95
82/83
97/81
5
>500
183
26
10
10
10
43/41/12
45/52/trace
165
b
c
a The reaction was carried out in benzene in the presence of the molybdenum catalyst (R)-Mo*. Initial concentration of the substrate. Isolated yields of
d
the products (2 and 3) and the recovered substrate (1). Enantiomeric excess of the recovered 1 was determined after converting them into 2 by a reaction
e
with the second-generation Grubbs’ catalyst. Calculated based on a first-order equation (ref 14).
proceeds very efficiently to afford planar-chiral ferrocenes in
high yield with excellent enantiomeric enrichment.
The ferrocene substrates for this study (rac-1, see Scheme
1) possess a trisubstituted η5-(C5H2-1-allyl-2,4-R1 ) ligand,
2
which constructs a planar-chiral environment in the ferrocenes,
and a monosubstituted η5-cyclopentadienyl ligand with an allylic
side chain. A readily available chiral molybdenum species (R)-
Mo* (Scheme 1)13 was chosen as an asymmetric metathesis
catalyst.
Enantioselectivity in the ARCM kinetic resolution was
strongly dependent on the structure of the allylic group in the
monosubstituted cyclopentadienyl moiety. Treatment of 1a with
the Mo* catalyst (5 mol %) for 15 min in benzene at 23 °C
yielded the corresponding ferrocenophane 2a in 73%, and the
unreacted 1a was recovered in 26%. To our disappointment,
however, the selectivity of the reaction was very low: 2a was
Figure 1. ORTEP drawing of (+)-(R)-2e with 40% thermal
ellipsoids. All hydrogen atoms are omitted for clarity.
nearly racemic (<1% ee) and the recovered 1a was only 2% ee
(Table 1, entry 1). The RCM reaction of the ferrocene 1b, which
nearly enantiomerically pure form (>99.5% ee) in 23% yield,
was with η5-(C5H4-crotyl), showed slightly better enantioselec-
and unreacted 1e of 78% ee was recovered in 30% yield. The
tivity and the ferrocenophane 2a of 12% ee was obtained in
krel for this reaction was >50014 (entry 5). Unfortunately,
44% yield (entry 2). Introduction of an η5-(C5H4-cinnamyl)
however, 47% of the substrate was converted to dimer 3e. The
ligand in 1c further improved enantioselectivity of the ARCM,
dimer 3e, which could be converted to the ferrocenophane 2e
although diluted conditions were required to suppress formation
by treatment with the second-generation Grubbs catalyst, was
of metathesized homodimer 3 (as a mixture of stereoisomers).
only 7% ee; that is, the dimer formation occurred with negligible
enantioselectivity. As before, dimerization was minimized in
A reaction of 1c at 80 °C (initial concentration of 1c ) 0.01
mol/L) gave 2a (66% ee, 26% yield) and recovered 1c (29%
the reaction under diluted conditions. A reaction of 1e with
ee, 53%). The krel value ([rate of fast-reacting enantiomer]/[rate
initial concentration of 0.005 mol/L affords 2e of 96% ee in
of slow-reacting enantiomer]) for this reaction was estimated
47% yield, and unreacted 1e of 95% ee was recovered in 46%
(entry 6). Although somewhat higher temperature (50 °C) was
required to gain a reasonable reaction rate under the high-
dilution conditions, enantioselectivity of the reaction was still
excellent (krel ) 183) and nearly perfect kinetic resolution of
rac-1e was achieved. As shown in entries 7 and 8, similarly
to be 6.414 (entry 3). A reaction of 1d, which was with η5-
C5H4CH2CHdCMe2, produced the dimer 3d in 38% as a sole
metathesis product and 2a was not detected (entry 4). The
recovered 1d was only 7% ee; that is, kinetic resolution of 1d
at the dimerization was not very efficient.
It was found that the enantioselectivity was dramatically
improved by introducing a η5-(C5H4-methallyl) moiety in the
ferrocene substrates. The RCM reaction of 1e at 23 °C (initial
concentration of 1e ) 0.1 mol/L) proceeded with excellent
enantioselectivity. The bridged ferrocene 2e was obtained in
high levels of enantioselectivity and reaction efficiency were
observed for kinetic resolution of 1f (krel ) 26) and 1g (krel
165) also under the optimized conditions.
)
Single-crystal X-ray crystallography revealed that absolute
configuration of the ARCM product 2e (Table 1, entry 5;
>99.5% ee), which was dextrorotatory ([R]30 +22 (c 0.50 in
D
(11) For examples of metathesis reactions of metallocene substrates,
see: (a) Hu¨erla¨ndere, D.; Kleigrewe, N.; Kehr, G.; Erker, G.; Fro¨hlich, R.
Eur. J. Inorg. Chem. 2002, 2633. (b) Sierra, J. C.; Hu¨erla¨nder, D.; Hill,
M.; Kehr, G.; Erker, G.; Fro¨hlich, R. Chem. Eur. J. 2003, 9, 3618. (c)
Kuwabara, J.; Takeuchi, D.; Osakada, K. Organometallics 2005, 24, 2705.
(d) Bauer, E. B.; Gladysz, J. A. In Handbook of Metathesis; Grubbs, R. H.,
Ed.; Wiley-VCH: Weinheim, 2003; Vol. 2, Chapter 2.11, p 403.
(12) For reviews of asymmetric olefin metathesis, see: (a) Hoveyda, A.
H.; Schrock, R. R. Chem. Eur. J. 2001, 7, 945. (b) Schrock, R. R.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2003, 42, 4592. (c) Hoveyda, A. H. In
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003;
Vol. 2, Chapter 2.3, p 128.
CHCl3)), was R, as shown in Figure 1. The configurations of
other ARCM products were assigned by analogy.
For highly enantioselective kinetic resolution of rac-1, an allyl
group in a trisubstituted cyclopentadienyl needs to be more
reactive than an allylic substituent in a monosubstituted cyclo-
pentadienyl. When the (R)-Mo* species approaches rac-1a,
initial metathesis occurs with the less crowded C5H4-allyl moiety
preferentially to form a diastereomeric mixture of (Ra,Rp)- and
(Ra,Sp)-4 (“Ra” represents absolute configuration of the axially
chiral biaryl moiety in Mo*) and formation of 5 is unfavorable
(Scheme 2, top). Whereas the allyl group in C5H4-allyl is remote
(13) Aeilts, S. L.; Cefalo, D. R.; Bonitatebus, P. J., Jr.; Houser, J. H.;
Hoveyda, A. H.; Schrock, R. R. Angew. Chem., Int. Ed. 2001, 40, 1452.
(14) (a) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1998, 18, 249. (b)
Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974.
from the planar-chiral η5-C5H2 Bu2(allyl) moiety, initial me-
t

Communications
Scheme 2. Plausible Stereochemical Pathways of the
Organometallics, Vol. 25, No. 22, 2006 5203
racemic form. On the other hand, with a less reactive methallyl
group in a monosubstituted Cp in place of the allyl group, the
reaction between (R)-Mo* and rac-1e takes place at the allyl
group in the planar-chiral trisubstituted Cp preferentially and
formation of 7 is minor. While (Ra,Rp)-6 is transformed into
(R)-2e smoothly via RCM, the epimeric (Ra,Sp)-6 is forced to
take an unfavorable conformation due to the steric repulsion
Mo-Catalyzed ARCM Kinetic Resolution of 1
t
t
t
between a Bu group in η5-C5H2 Bu2(allyl) and a Bu group in
the chiral biaryl ligand in (R)-Mo* to liberate (S)-1e (Scheme
2, bottom).
In summary, we have developed an effective method for
kinetic resolution of racemic planar-chiral ferrocene derivatives
via molybdenum-catalyzed asymmetric ring-closing metathesis.
This is the first example of highly enantioselective metal-
catalyzed induction of planar chirality in metallocene substrates.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan, and
the Nagase Science and Technology Foundation (to M.O.).
Supporting Information Available: Detailed experimental
procedures, compound characterization data, and crystallographic
data (CIF file). This material is available free of charge via the
Internet at http://pubs.acs.org.
tathesis with (R)-Mo* takes place with negligible stereoselec-
tivity. Following the RCM step in 4 is an intramolecular process,
and thus both (Ra,Rp)- and (Ra,Sp)-4 can be smoothly transformed
into the corresponding ferrocenoephanes to give 2a in nearly
OM0608298