Diastereoselective ruthenium-Cp complexation of enantiopure arene compounds possessing stereogenic benzylic alcohol functionalities

Article abstract of DOI:10.1021/ol010197f

Figure presented R = OMe, Me, Me₃Si 84-94 % up to 95/5 dr Enantiopure (arene)ruthenium compounds possessing a stereogenic benzylic alcohol functionality were stereoselectively synthesized by diastereoselective ruthenium-Cp complexation to a distinct arene face. This diastereoselective ruthenium-Cp complexation was further extended to biaryl compounds linked with a six-membered lactone bridge for the synthesis of enantiomerically pure, axially chiral biaryls.

Full text of DOI:10.1021/ol010197f

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3667-3670
Diastereoselective Ruthenium−Cp
Complexation of Enantiopure Arene
Compounds Possessing Stereogenic
Benzylic Alcohol Functionalities
Ken Kamikawa,† Masaru Furusyo,‡ Takahiro Uno,† Yasuko Sato,†
,†
Atutoshi Konoo,§ Gerhard Bringmann, and Motokazu Uemura*
Department of Chemistry, Faculty of Integrated Arts and Sciences, Osaka Prefecture
UniVersity, Sakai, Osaka 599-8531, Japan, CAE Research Center, Sumitomo Electric
Industries Ltd., 1-7 Hikaridai, Seika, Soraku-gun, Kyoto 619-0237, Japan,
Department of Material Sciences, Faculty of Engineering, Osaka Prefecture
UniVersity, Sakai, Osaka 599-8531, Japan, and Institute fu¨r Organische Chemie,
UniVersita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany
uemura@ms.cias.osakafu-u.ac.jp
Received September 4, 2001
ABSTRACT
Enantiopure (arene)ruthenium compounds possessing a stereogenic benzylic alcohol functionality were stereoselectively synthesized by
diastereoselective ruthenium−Cp complexation to a distinct arene face. This diastereoselective ruthenium−Cp complexation was further extended
to biaryl compounds linked with a six-membered lactone bridge for the synthesis of enantiomerically pure, axially chiral biaryls.
(η6-Arene)transition metal complexes are well-recognized as
versatile intermediates in organic synthesis as a consequence
of their electron-withdrawing ability and steric bulkiness of
the transition metal. Particularly, η6-arene chromium com-
plexes have been most extensively studied in organic
reactions.1 In contrast to the arene chromium complexes,
isoelectronic (η6-arene)ruthenium Cp+ complexes have re-
ceived comparatively little attention despite the mild condi-
tions for their preparation and air stability.2 Furthermore, η6-
arene transition metal complexes exist in two enantiomeric
forms based on a planar chirality when the arene ring is
substituted with different substituents at the 1,2- or 1,3-
positions. Although the synthesis of planar chiral Ru
complexes with unsymmetrically substituted cyclopentadienyl
ligand has been studied,3 there are only few efforts for the
preparation of planar chiral enantiomerically pure (η6-arene)-
ruthenium complexes with different substituents on the arene
ring.4 As part of our program on asymmetric syntheses
† Faculty of Integrated Arts and Sciences, Osaka Prefecture University.
‡ Sumitomo Electric Industries Ltd.
(2) Representative examples: (a) Pigge, F. C.; Fang, S.; Rath, N. P. Org.
Lett. 1999, 1, 1851-1854. Tetrahedron Lett. 1999, 40, 2251-2254. (b)
Pearson, A. J.; Chelliah, M. V. J. Org. Chem. 1998, 63, 3087-3098. (c)
Janetka, J. W.; Rich, D. H. J. Am. Chem. Soc. 1997, 119, 6488-6495. (d)
Komatsuzaki, N.; Uno, M.; Kikuchi, H.; Takahashi, S. Chem. Lett. 1996,
677-678. (e) Gill, T. P.; Mann, K. R. Organometallics 1982, 1, 485-488.
(f) Moriarty, R. M.; Gill, U. S.; Ku, Y. Y. J. Organomet. Chem. 1988, 350,
157-190. (g) Pearson, A. J.; Bignan, G. Tetrahedron Lett. 1996, 37, 735-
738. (h) Pearson, A. J.; Gelormini, A. M. J. Org. Chem. 1994, 59, 4561-
4570.
§ Faculty of Engineering, Osaka Prefecture University.
Universita¨t Wu¨rzburg.
(1) (a) Semmelhack, M. F. In ComprehensiVe Organometallic Chemistry
II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Elsevier Science,
Ltd.: Oxford, 1995; Vol. 12, pp 979-1015, 1017-1038. (b) Davies, S.
G.; McCarthy, T. D. In ComprehensiVe Organometallic Chemistry II; Abel,
E. W., Stone, F. G. A., Wilkinson, G., Eds.; Elsevier Science, Ltd.: Oxford,
1995; Vol. 12, pp 1039-1070.
10.1021/ol010197f CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/25/2001

utilizing the planar chiral arene transition metal complexes,
we herein report on the stereoselective synthesis of planar
chiral (arene)ruthenium Cp+ complexes of 2-substituted
benzyl alcohol derivatives and their synthetic application to
axially chiral biaryls.
Among two proposed transition states A and B, the confor-
mation B is minimized for nonbonded interaction between
the ortho-substituent and the methyl groups (Figure 1).6
We initially studied a diastereoselective ruthenium com-
plexation of 2-substituted secondary benzyl alcohols. 1-(2-
Methoxyphenyl)ethanol (1a, Scheme 1) was heated to reflux
Scheme 1
Figure 1. Proposed Transition State
The diastereoselective ruthenium Cp complexation of the
secondary benzyl alcohols was further extended to biaryl
compounds linked with a six-membered lactone bridge. One
of us already reported that the related biaryls connected with
δ-lactone bridge gave the corresponding chromium or
ruthenium complexation products.7 However, these transition
metal-coordinated biaryls were obtained as axially equili-
brated compounds without distinction of the arene face in
racemic form. Furthermore, most of δ-lactone bridged biaryls
without the transition metal coordination to the arene ring
are configurationally unstable at the biaryl axis.8 However,
these nonchiral axially equilibrated compounds are useful
intermediates for asymmetric synthesis of axially chiral
biaryls. Thus, the δ-lactone rings of axially equilibrated
biaryls were opened with chiral O-nucleophiles via dynamic
kinetic resolution to give optically active biaryls developed
by the Wu¨rzburg group.8 To prepare the optically active
RuCp+ complexes of the biaryls connected with δ-lactone
by using diastereoselective complexation with the distinct
arene face, δ-lactone bridged biaryls with an enantiomerically
active secondary benzyl alcohol function were initially
prepared (Scheme 2). Catalytic asymmetric reduction9 of
acetophenone derivative 4a with a chiral (S)-oxazaborolidine
and BH3‚Me2S gave the (R)-alcohol 5a with 97% ee in a
quantitative yield, and subsequent palladium-catalyzed in-
tramolecular coupling with a combination of Pd(OAc)2 and
2-di-tert-butylphosphinobiphenyl10 produced the desired dia-
stereomeric biaryl δ-lactones 6a and 6a′ as an inseparable
2:1 atropisomeric mixture in 69% yield. The atropisomer-
ization barrier of these two diastereomers was measured by
with [CpRu(CH3CN)3]PF6 in dichloroethane to give a
*
(Sp ,S*)-Ru complex 2a in 93% yield with 92/8 dr (Table 1,
Table 1. Diastereoselective Ruthenium Complexation Reaction
of 2-Substituted Secondary Benzyl Alcohols 1
entry
compd
R
ratio (2: 3)
yield (%)
1
2
3
1a
1b
1c
OMe
Me
SiMe3
92:8
94:6
95:5
93
84
86
entry 1). With more bulky, methyl- or trimethylsilyl-
substituted phenylethanols, the diastereoselectivities of
CpRu+ complexation increased slightly (entries 2 and 3). The
relative configuration of 2a was determined by X-ray
crystallography after acetylation.5 This diastereoselective
ruthenium complexation to the distinct arene face occurs via
an interaction of the ruthenium to the benzylic oxygen atom.
(3) (a) Katayama, T.; Matsushima, Y.; Onitsuka, K.; Takahashi, S. Chem
Commun. 2000, 2337-2338. (b) Trost, B. M.; Vidal, B.; Thommen, M.
Chem. Eur. J. 1999, 5, 1055-1069. (c) Komatsuzaki, N.; Uno, M.; Kikuchi,
H.; Takahashi, S. Chem. Lett. 1996, 677-678. (d) Uno, M.; Ando, K.;
Komatsuzaki, N.; Tsudo, T.; Tanaka, T.; Sawada, M.; Takahashi, S. J.
Organomet. Chem. 1994, 473, 303-311. (e) Uno, M.; Ando, K.; Ko-
matuzaki, N.; Takahashi, S. J. Chem. Soc., Chem. Commun. 1992, 964-
965.
(4) Thermal replacement of the acetonitrile ligand from the planar chiral
substituted Cp-Ru(MeCN)3 system to prochiral arenes gave planar chiral
arene ruthenium Cp complexes with moderate selectivity; Komatsuzaki,
N.; Kikuchi, H.; Yamamoto, M.; Uno, M.; Takahashi, S. Chem. Lett. 1998.
445-446.
(5) Crystal structure data of acetylation of 2a: experimental formula )
C16H19O3RuPF6, FW ) 505.36, orthorhombic, space group P212121 (No.
19), a ) 14.600(3) Å, b ) 17.926(2) Å, c ) 7.136(2) Å, V ) 1867.7(5)
Å3, Z ) 4, Dcalcd ) 1.797 g cm-3. Crystallographic data (excluding structure
factors) for the structure reported in this paper have been deposited with
Cambridge Crystallographic Data Center as supplementary publication no.
CCDC-165780. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax (+44)
1223-336-033; e-mail deposit@ccdc.cam.ac.uk).
(6) Uemura, M. In AdVances in Metal-Organic Chemistry; Liebsekind,
L. S., Ed.; JAI Press Ltd.: Greenwich, CT, 1991; Vol. 2, pp 195-245.
(7) (a) Bringmann, G.; Heubes, M.; Breuning, M.; Go¨bel, L.; Ochse,
M.; Scho¨ner, B.; Schupp, O. J. Org. Chem. 2000, 65, 722-728. (b)
Bringmann, G.; Wuzik, A.; Stowasser, R.; Rummey, C.; Go¨bel, L.; Stalke,
D.; Pfeiffer, M.; Schenk, W. A. Organometallics 1999, 18, 5017-5021.
(c) Bringmann, G.; Go¨bel, L. Inorg. Chim. Acta 1994, 222, 255-260.
(8) The corresponding homologous seven-membered lactone biaryls are
stable for an axial equilibration. (a) Bringmann, G.; Hinrichs, J.; Henschel,
P.; Peters, K.; Peters, E.-M. Synlett 2000, 1822-1824. (b) Bringmann, G.;
Hartung, T.; Kro¨cher, O.; Gulden, K.-P.; Lange, J.; Burzlaff, H. Tetrahedron
1994, 50, 2831-2840. (c) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis
1999, 4, 525-558.
(9) (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. Engl. 1998, 37,
1986-2012. (b) Xavier, L. C.; Mohan, J. J.; Mathre, D. J.; Thompson, A.
S.; Carroll, J. D.; Corley, E. G.; Desmond, R. Org. Synth. 1991, 74, 50-
71.
(10) (a) Aranyous, A.; Old, D. W.; Kiyomori, A.; Wolf, J. P.; Sadighi,
J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369-4378. (b) Wolfe,
J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1999, 38, 2413-2416.
3668
Org. Lett., Vol. 3, No. 23, 2001

Scheme 2a
Table 2. Summary of ab Initio Calculations of Biaryl Lactone
free
enthalpy
zero point corrn (H) corrn (H)
energy (H) energy (H) at 298 K at 298 K
energy
total
entry compd
1
2
3
6a
6a ′
-843.80850
-843.81005
0.26407
0.26383
0.26439
0.28077
0.28056
0.28018
0.22204
0.22168
0.22253
6a (TS) -843.78257
a Reagents and conditions: (a) BH3‚Me2S, (S)-oxazaborolidine
(20 mol %), THF, rt (99%, 97% ee from 4a; 99%, 98% ee from
4b), (b) Pd(OAc)2, (10 mol %), 2-(di-tert-butylphosphino)biphenyl
(20 mol %), NaOAc, DMA, 100 °C (69% from 5a; 60% from 5b),
(c) [CpRu(CH3CN)3]PF6, (CH2Cl)2, reflux, (51% from 6a and 6a′;
48% from 6b or 6b′), (d) NaOMe, MeOH, (98% from 7a; 99%
from 7b), (e) hν, CH3CN, (95% from 8a; 98% from 8b).
Ru(II)+Cp complexation of the diastereomeric mixture 6a
and 6a′. Surprisingly, ruthenium complex 7a was obtained
as a single axially chiral diastereomer in 51% yield13 without
formation of any stereo- and regioisomers by treatment with
[CpRu(CH3CN)3]PF6 under the same conditions.14 The
formation as a single diastereomer is in sharp contrast to
the previous report7b,c that the related δ-lactone-linked biaryl
compound gave an inseparable mixture of chromium com-
plexes. The configuration of 7a was determined by X-ray
analysis.15 The Cp ruthenium fragment was coordinated to
the arene ring substituted with the electron-donating hy-
droxymethyl and methoxy groups via an interaction of the
ruthenium with the benzylic oxygen. The axial chirality of
dynamic 1H NMR studies of coalescence of two independent
signals at 110 °C. The activation free energy was calculated
as 17.01 kcal mol-1 on the basis of the Eyring equation.11
Theoretical calculations12 showed that the diastereomer 6a
was 1.12 kcal mol-1 more stable than 6a′ in total energy,
and the atropisomerization barrier was estimated as 17.77
kcal mol-1 (Table 2), in a good agreement with the
experimental value. Thus, these two axial diastereomers can
be observed at room temperature. With the optically active
δ-lactone-bridged biaryl in hand, we next studied the
(13) The described values are purified yields of crude products (∼70%)
after a recrystallization for a removal of contaminant ruthenium reagent
along with 10% yield of the starting materials. The diastereoselectivity of
the ruthenium complexation products was determined of the crude products
by NMR spectra, and the stereo- and regioisomers were not observed by
1H NMR spectra of the crude products of 7a and 7b.
(11) Ernst, L. Chem. Unserer Zeit 1983, 17, 21-31.
(12) Geometry optimizations were carried out with B3LYP hybrid density
functional theory on using 6-31G* (C, H, O) and LACVP (Ru) basis sets
with the Gaussian 98 and Jaguar V3.5 suite of programs.
(14) The corresponding Cr(CO)3 complex was not formed by treatment
of 6 with Cr(CO)6 or (naphthalene)Cr(CO)3.
Org. Lett., Vol. 3, No. 23, 2001
3669

the complex 7a was found to be the (S)-configuration. The
complex 7a is by 2.1 kcal mol-1 more stable than the
corresponding (R)-configured diastereomer 7a′ by ab initio
calculations (Table 3).12 This value is larger than the
complex 7b without the formation of any stereo- and
regioisomers in 48% yield13 under the same conditions. In
this way, the equilibrated axially diastereomeric biaryls linked
with the δ-lactone ring bridge gave a thermodyanamically
stable atropisomeric compound as a single isomer by
ruthenium complexation to the distinct arene face.17
With the axially chiral ruthenium-complexed δ-lactone
biaryls in hand, we next focused on the ring opening of
δ-lactones 7a and 7b with nonchiral reagents. The ruthenium
complexes 7a and 7b were treated with NaOMe in methanol
at room temperature to give a single diastereomer18 of axially
chiral ortho-tetra-substituted biaryl ruthenium complexes 8a
and 8b in 98% and 99% yields, respectively. The relative
configuration was elucidated by differential NOE experi-
ments and an opposite face attack of nucleophile to the
transition metal fragment. Thus, a 7% NOE was observed
between the methyl group on the ruthenium-free arene ring
and the Cp ring of 8a. Finally, demetalation of the complexes
8a and 8b gave axially chiral biaryls 9a and 9b in good
yields. Furthermore, stereoselective reduction of the lactone
ring of 7b with LiAlH4 gave the corresponding axially chiral
biaryl as a single diastereomer in 99% yield.19
Table 3. Summary of ab Initio Calculation of Ruthenium
Complex
enthalpy free energy
total
zero point corrn (H) corrn (H)
entry compd energy (H) energy (H) at 298 K
at 298 K
1
2
7a
7a ′
-1131.03520
-1131.03916
0.37604
0.37649
0.39619
0.39754
0.32953
0.32776
difference (1.12 kcal mol-1) of the total energies between
the pre-ruthenium complexation diastereomers 6a and 6a′.
Although a precise mechanism for the formation of ruthe-
nium complex 7a as a single axial diastereomer is not clear
at the present time, complex 7a might be formed as a
thermodynamically stable compound via axial isomerization
of the diastereomeric (R)-axial ruthenium complex derived
from the diastereomer 6a′ under the reaction conditions. An
alternative mechanism may also be considered: the ruthe-
nium complexation takes place from a distinct face of only
diastereomer 6a via a dynamic kinetic resolution of the
axially equilibrated diastereomers 6a and 6a′. We further
examined the diastereoselective ruthenium complexation of
a sterically less substituted biaryl lactone, the methoxy
analogue 6b. The palladium-catalyzed coupling of optically
active alcohol 5b produced the desired biaryl as a single
diastereomer in 60% yield without detection of any stereo-
isomers. A rapid interconversion between 6b and 6b′ is
considered feasible by decreasing a steric demand.16 Simi-
larly, the ruthenium complexation of the diastereomeric
mixture of 6b and 6b′ gave the single axially chiral ruthenium
In conclusion, we have developed a diastereoselective
ruthenium complexation of 2-substituted secondary benzyl
alcohol derivatives to the distinct arene face and asymmetric
synthesis of enantiomerically pure axially chiral biaryls.
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research on Priority Areas (A)
Exploitation of Multi-Element Cyclic Molecules from the
the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Supporting Information Available: Experimental pro-
cedures and characterization data of products. This material
is available free of charge via Internet at http://pus.acs.org.
OL010197F
(17) A naphthyltetrahydroisoquinoline skeleton with a chiral center
having sterically bulky substituents and specific nitrogen substitution could
also fix the axial axis of δ-lactone-bridged biaryls by palladium-catalyzed
cyclization: see ref 8c.
(18) The δ-lactone ring opening of the ruthenium-uncomplexed biaryls
6 with NaOMe gave the diastereomeric mixture of axially atropisomeric
biaryls (dr ) 7:3 for 6a; 1:1 for 6b) on the basis of the axially equilibrated
ratio of 6a and 6b.
(19) Interestingly, a related ruthenium complex biaryl lactone ring could
be opened only with O-nucleophiles: see ref 7b. We are now investigating
the reason for these different reactivities with hydride reduction between
the related ruthenium complexes.
(15) Crystal structure data of 7a: experimental formula ) C22H21O4-
PF6Ru, FW ) 595.44, orthorhombic, space group Pbcn (No. 60), a )
16.953(3) Å, b ) 15.441(2) Å, c ) 20.454(2) Å, V ) 5354(2) Å3, Z ) 8,
Dcalcd ) 1.477 g cm-3. Crystallographic data (excluding structure factors)
for the structure reported in this paper have been deposited with Cambridge
Crystallographic Data Center as supplementary publication no. CCDC-
165781.
(16) Theoretical calculations (B3LYP/6-31*) showed that the atropo-
isomerization barrier between axial diastereomers 6b and 6b′ is estimated
at 8.68 kcalmol-1
.
3670
Org. Lett., Vol. 3, No. 23, 2001