Enantioselective ruthenium-catalyzed ring-closing metathesis

Article abstract of DOI:10.1021/ol0165692

(equation presented) The first enantioselective ruthenium olefin metathesis catalysts have been prepared, and high enantiomeric excesses (up to 90%) are observed in the desymmetrization of achiral trienes. A model consistent with the stereochemical outcom

Full text of DOI:10.1021/ol0165692

ORGANIC
LETTERS
2
001
Vol. 3, No. 20
225-3228
Enantioselective Ruthenium-Catalyzed
Ring-Closing Metathesis
3
T. Jon Seiders, D. William Ward, and Robert H. Grubbs*
Arnold and Mabel Beckman Laboratory of Chemical Synthesis,
DiVision of Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, California 91125
rhg@its.caltech.edu
Received August 13, 2001
ABSTRACT
The first enantioselective ruthenium olefin metathesis catalysts have been prepared, and high enantiomeric excesses (up to 90%) are observed
in the desymmetrization of achiral trienes. A model consistent with the stereochemical outcome of the reactions is described and suggests
side-on olefin binding and reorganization of the halide ligands.
Over the past decade, olefin metathesis has emerged as a
functional group tolerance and require rigorous exclusion of
air and moisture, the development of enantioselective me-
tathesis catalysts based on ruthenium is expected to expand
dramatically the scope and utility of these transformations.
powerful carbon-carbon bond-forming reaction that is
1
widely used in organic synthesis and polymer science. A
major advance in this field was the development of chiral
2
6
molybdenum catalysts that exhibit high enantioselectivity
Herein, we report chiral N-heterocyclic carbene (NHC)
3
4
7
in a variety of ring-closing and ring-opening metathesis
complexes of ruthenium that exhibit high enantioselectivity
5
reactions. However, these molybdenum-based systems
(up to 90% ee) in the ring-closing metathesis of achiral
3
b
require specific substrate-to-catalyst matching, necessitating
reaction optimization and the availability of a number of
catalysts. Additionally, because these systems lack extensive
trienes.
In light of studies on the IMesH
(IMesH ) 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene) that
2
/ruthenium system
2
suggest that the NHC ligand does not dissociate from
ruthenium during metathesis, desymmetrization of the
IMesH ligand was effected in the development of chiral
2
(
1) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
8
(
b) F u¨ rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. Ivin, K. J.
J. Mol. Catal. A: Chem. 1998, 133, 1-16. (c) Randall, M. L.; Snapper, M.
L. J. Mol. Catal. A: Chem. 1998, 133, 29-40. Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413-4450.
(5) For an in situ preparation of chiral molybdenum catalysts, see: Aeilts,
S. L.; Cefalo, D. R.; Bonitatebus, P. J.; Houser, J. H.; Hoveyda, A. H.;
Schrock, R. R. Angew. Chem., Int. Ed. 2001, 40, 1452-1456.
(6) For previous reports of chiral NHC metal complexes, see: (a) Clyne,
D. S.; Jin, J.; Genest, E.; Gallucci, J. C.; RajanBabu, T. V. Org. Lett. 2000,
2, 1125-1128. (b) Enders, D.; Gielen, H.; Breuer, K. Tetrahedron:
Asymmetry 1997, 8, 3571-3574. (c) Herrmann, W. A.; Goossen, L. J.;
K o¨ cker, C.; Artus, G. R. J. Angew. Chem., Int. Ed. Engl. 1996, 35, 2805-
2807. (d) Herrmann, W. A.; Goossen, L. J.; Spiegler, M. Organometallics
1998, 17, 2162-2168. (e) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66,
3402-3415.
(2) For a review of molybdenum-catalyzed enantioselective metathesis,
see: Hoveyda, A. H.; Schrock, R. R. Chem. -Eur. J. 2001, 7, 945-950.
(3) (a) Alexander, J. B.; La, D. S.; Cefalo, D. R.; Hoveyda, A. H.;
Schrock, R. R. J. Am. Chem. Soc. 1998, 120, 4041-4042. (b) La, D. S.;
Alexander, J. B.; Cefalo, D. R.; Graf, D. D.; Hoveyda, A. H.; Schrock, R.
R. J. Am. Chem. Soc. 1998, 120, 9720-9721. (c) Cefalo, D. R.; Kiely, A.
F.; Wuchrer, M.; Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 2001, 123, 3139-3140. (d) Zhu, S. S.; Cefalo, D. R.; La, D.
S.; Jamieson, J. Y.; Davis, W. M.; Hoveyda, A. H.; Schrock, R. R. J. Am.
Chem. Soc. 1999, 121, 8251-8259.
(4) (a) La, D. S.; Ford, J. G.; Sattely, E. S.; Bonitatebus, P. J.; Schrock,
(7) For preparations, see: (a) Scholl, M.; Trnka, T. M.; Morgan, J. P.;
Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247-2250. (b) Scholl, M.; Ding,
S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956. (c) Huang, J.
K.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem. Soc. 1999,
R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 11603-11604. (b)
Weatherhead, G. S.; Ford, J. G.; Alexanian, E. J.; Schrock, R. R.; Hoveyda,
A. H. J. Am. Chem. Soc. 2000, 122, 1828-1829.
1
0.1021/ol0165692 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/08/2001

ruthenium metathesis catalysts. Although the mesityl rings
of the NHC ligand are readily replaced with chiral substit-
uents through synthesis from commercially available chiral
alkylamines, preliminary investigations into the selectivity
Scheme 1
9
of these ruthenium complexes are not promising. Alterna-
tively, synthesis of the NHC from commercially available
chiral diamines introduces chirality to the imidazole ring,
but the stereocenters of the ligand are remote from the metal
center. By replacing the mesityl substituents with mono-o-
substituted aryl groups, a steric effect is expected to more
effectively transfer the stereochemistry of the ligand nearer
the metal center by placing the o-substitutents of the aryl
groups in an arrangement anti to the substituents on the
imidazole ring (Figure 1).
solids and are easily purified on the benchtop by column
1
3
chromatography. The bromide and iodide analogues of
these complexes are generated in situ by the addition of
excess LiBr or NaI, respectively.
2
Figure 1. Desymmetrization of the IMesH /ruthenium system.
8
c
Although crystals have not been forthcoming for com-
plexes 8b,c, crystallographic evidence of the conformation
of the chiral NHC ligands has been obtained by conversion
of complex 8b to bis(pyridine) adduct 9. The crystal
structure of complex 9 (Figure 2) shows that the NHC ligand
The enantiomerically pure ruthenium complexes are easily
prepared in three steps from commercially available starting
materials (Scheme 1). Diamines 3a-c and 4a-c are syn-
thesized by palladium-catalyzed amination of the appropriate
aryl bromides with (1R,2R)-1,2-diaminocyclohexane (1) or
1
4
(
1R,2R)-diphenylethylenediamine (2).10 The resulting di-
amines are condensed with triethyl orthoformate and am-
monium tetrafluoroborate to produce the corresponding
11
imidazolium tetrafluoroborate salts 5a-c and 6a-c. These
1
2
salts are treated with potassium hexafluoro-tert-butoxide
followed by (PCy (Cl) RudCHPh to displace a single PCy
3
)
2
2
3
and generate the desired chiral complexes 7a-c and 8a-c
in good yields. Complexes 7a-c and 8a-c are air-stable
1
21, 2674-2678. (d) Jafarpour, L.; Nolan, S. P. J. Organomet. Chem. 2001,
17, 17-27. (e) Weskamp, T.; Kohl, F. J.; Gleich, D.; Herrmann, W. A.
6
Angew. Chem., Int. Ed. 1999, 38, 2416-2419. For reactivity studies, see:
(f) Bielawski, C. W.; Grubbs, R. H. Angew. Chem., Int. Ed. 2000, 39, 2903-
2
906. (g) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J.
Am. Chem. Soc. 2000, 122, 3783-3784. (h) Choi, T. L.; Chatterjee, A. K.;
Grubbs, R. H. Angew. Chem., Int. Ed. 2001, 40, 1277-1279.
(
8) (a) Huang, J. K.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am.
Chem. Soc. 1999, 121, 2674-2678. (b) Herrmann, W. A.; K o¨ cher, C.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2162-2187. (c) Sanford, M. S.;
Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 6543-6554.
Figure 2. X-ray crystal structure of 9 (50% probability ellipsoids).
Selected bond lengths and angles for 9: Ru(1)-C(19) 1.871 Å,
Ru(1)-C(1) 2.031 Å, Ru(1)-N(3) 2.352 Å, Ru(1)-N(4) 2.187 Å,
C(8)-C(19) 2.758 Å, Cl(1)-Ru(1)-Cl(2) 175°, C(19)-Ru(1)-
N(3) 166°, C(1)-Ru(1)-N(4) 180°, Cl(1)-Ru(1)-C(19)-C(17)
46°.
(9) Ruthenium complexes of 1,3-diisopinocampheol-4,5-dihydroimidazol-
2
-ylidene were tested with all substrates reported here, but exhibit only
modest selectivity (for ligand synthesis, see ref 6e).
10) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc.
(
Chem. Res. 1998, 31, 805-818. (b) Yang, B. H.; Buchwald, S. L. J.
Organomet. Chem. 1999, 576, 125-146.
(
11) Saba, S.; Brescia, A.-M.; Kaloustain, M. K. Tetrahedron Lett. 1991,
2
is approximately C -symmetric with the o-methyl group
3
2, 5031-5034.
(
12) If potassium tert-butoxide is used, the yields of 7 and 8 are
oriented anti to the phenyl substituent of the imidazole ring.
Additionally, the phenyl group of the benzylidene is oriented
anti to the o-methyl substituent of the proximal aryl ring.
dramatically reduced and a tert-butoxide adduct of ruthenium forms:
Sanford, M. S.; Henling, L. M.; Day, M. W.; Grubbs, R. H. Angew. Chem.,
Int. Ed. 2000, 39, 3451-3453.
3226
Org. Lett., Vol. 3, No. 20, 2001

-
-
This anti-anti arrangement suggests that the stereochemistry
of the phenyl substituents on the imidazole ring is effectively
transferred to the metal center.
With a series of catalysts in hand, the enantioselective
desymmetrization of substrates 10-12 to dihydrofurans 13-
catalyst 8c from Cl (23% ee, entry 3) to I (39% ee, entry
5) further improves the enantioselectivity. Although the
enantioselectivity increases upon changing to the iodide, a
marked reduction in the conversion to 13 is observed,
presumably due to the instability of the diiodoruthenium
1
6
15 is effected (Scheme 2). Substrates 10-12 feature a
methylidene complex generated in the course of this
reaction.
To prevent the generation of the methylidene complex and
to explore the substrate requirements for high enantioselec-
tivity, trisubstituted substrates 11 and 12 are tested. In the
case of the (Z)-trisubstituted olefin 11, conversions are always
high, but enantioselectivites are low (<36% ee). However,
in the case of (E)-trisubstituted olefin 12, high enantiose-
lectivity and high conversion are achieved (90% ee, entry
Scheme 2
1
1). Importantly, neither solvent (THF, dichloromethane,
benzene) nor temperature (-15 °C, 0 °C, 38 °C) has a
significant effect on the enantioselectivity of these systems.
Additionally, the activity and stability of catalysts 8b and
8
2
c are similar to those of the IMesH /ruthenium system
monosubstituted central olefin with which the catalyst
undergoes the initial metathesis reaction,15 and two di- or
trisubstituted pendant olefins with which the stereochemically
defining cyclization step occurs. A preliminary series of
reactions, the desymmetrization of substrate 10, reveals three
distinct trends in catalyst selectivity (Table 1). First, catalysts
(rigorous exclusion of air and moisture is not required).
Previous studies suggest a 14-electron, four-coordinate
species as the active intermediate in the metathesis cycle,17
but the geometry of this intermediate and the subsequent
olefin complex intermediates remains unknown. Three dif-
ferent conformations of the intermediate olefin complex have
1
8
been proposed (Figure 3): A, in which one halide ligand
Table 1. Enantioselective Desymmetrization of Trienes 10-12
by Catalysts 8a-c
Figure 3. Possible geometries of olefin complex.
is bound trans to the L-type ligand; B, in which the chlorides
adopt a cis arrangement in the alkylidene-halide-olefin
plane; and C, in which the olefin binds trans to the L-type
ligand. Of these conformations, only C is inconsistent with
the observed stereochemical outcome of the desymmetriza-
tion of substrates 10-12. Although geometry B cannot be
(
13) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A.
H. J. Am. Chem. Soc. 1999, 121, 791-799.
14) Similar results are observed in achiral NHC/ruthenium bis(pyridine)
a
Conditions: 2.5 mol % of catalyst, 55 mM substrate in CH2Cl2, 38
C. When halide salt is added: 5 mol % of catalyst, 100 mol % of halide
(
°
b
complexes, see: (a) Sanford, M. S.; Love, J. A.; Grubbs, R. H., submitted.
(b) Sanford, M. S. Ph.D. Thesis, California Institute of Technology,
Pasadena, CA, 2001.
salt, 55 mM substrate in THF, 38 °C. Absolute stereochemistry determined
by comparison with GLC chromatograms reported in ref 3b. Measured
by chiral GLC (Chiraldex GTA Alltech) with toluene as an internal standard.
c
(15) Ulman, M.; Grubbs, R. H. Organometallics 1998, 17, 2484-2489.
(16) Ulman, M.; Grubbs, R. H. J. Org. Chem. 1999, 64, 7202-7207.
(17) Sanford, M. S.; Ulman, M.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
1
2
23, 749-750.
(
18) (a) Trnka, T. M.; Day, M. W.; Grubbs, R. H. Organometallics 2001,
prepared from (1R,2R)-diphenylethylenediamine (8a-c)
exhibit higher enantioselectivity (up to 23% ee) than those
prepared from (1R,2R)-1,2-diaminocyclohexane (7a-c) (<9%
ee). Second, replacement of the mesityl groups (8a, 15%
ee, entry 1) with o-methyl- (8b, 23% ee, entry 2) or
o-isopropylaryl groups (8c, 23% ee, entry 3) increases the
enantioselectivity. Third, changing the halide ligands of
0, 3845-3847. (b) Tallarico, J. A.; Bonitatebus, P. J.; Snapper, M. L. J.
Am. Chem. Soc. 1997, 119, 7157-7158. (c) Hinderling, C.; Baumann, H.;
Chen, P. Angew. Chem., Int. Ed. 1998, 37, 2685-2689. (d) Adlhart, C.;
Hinderling, C.; Baumann, H.; Chen, P. J. Am. Chem. Soc. 2000, 122, 8204-
8
214. (e) Bianchini, C.; Lee, H. M. Organometallics 2000, 19, 1833-1840.
(
f) Moers, F. G.; Langhout, J. P. J. Inorg. Nucl. Chem. 1977, 39, 591-
5
93. (g) Brown, L. D.; Barnard, C. F. J.; Daniels, J. A.; Mawby, R. J.;
Ibers, J. A. Inorg. Chem. 1978, 17, 2932-2935. (h) Dias, E. L.; Nguyen,
S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887-3897.
Org. Lett., Vol. 3, No. 20, 2001
3227

and apical halide is further consistent with the dramatic
increase in enantioselectivity observed upon changing the
-
-
-
halide from Cl to Br to I .
In conclusion, the first enantioselective ruthenium olefin
metathesis catalysts have been prepared, and high enanti-
oselectivities (up to 90% ee) are observed in the desymme-
trization of achiral trienes. A model consistent with the
stereochemical outcome of the reactions is described and
suggests side-on olefin binding and reorganization of the
halide ligands. An understanding of the olefin complex
geometry has implications in general mechanistic under-
standing and for the further development of enantioselective
metathesis catalysts and reactions. Furthermore, the ease of
handling and anticipated functional group tolerance of the
described ruthenium catalysts are expected to expand the
utility of enantioselective olefin metathesis in organic
synthesis by allowing access to a wide range of substrates.
Figure 4. Stereochemical model of catalyst 8c (configuration of
dihydrofuran 15).
Acknowledgment. This work was supported by the
National Institutes of Health. The authors also thank Lawrence
M. Henling and Dr. Michael W. Day for solving the crystal
structure of complex 9, Tina Trnka and Arnab Chatterjee
for supplying isopinocampheol catalyst, and Drs. Melanie
Sanford and Jennifer Love for many helpful discussions.
discounted, geometry A appears to be most consistent with
the observed ligand effects and stereochemical outcome of
these reactions. Geometries similar to that of A have been
observed crystallographically1 and computationally, and
three key features of stereochemical model A are consistent
with the observed selectivity (Figure 4). First, the alkylidene
substituent is oriented anti to the bulky NHC ligand. Second,
the tethered olefin binds to the front face of the complex to
avoid a steric interaction with the bulky o-isopropyl group
of the NHC ligand. Third, the unbound olefin (R in Figure
8a
18d
Supporting Information Available: Experimental details
for all new complexes, GC traces, and a complete table of
enantiomeric excesses for all substrates and catalysts. This
information is available free of charge via the Internet at
http://pubs.acs.org.
4) occupies the distal position relative to the apical halide;
this proposed steric interaction between the unbound olefin
OL0165692
3228
Org. Lett., Vol. 3, No. 20, 2001