Synthesis, resolution and crystallographic characterization of a new C2-symmetric planar-chiral bipyridine ligand: Application to the catalytic enantioselective cyclopropanation of olefins

Article abstract of DOI:10.1039/a909457a

The synthesis of a new C₂-symmetric planar-chiral bipyridine ligand is described, as well as its application to the enantioselective Cu(I)-catalyzed cyclopropanation of olefins.

Full text of DOI:10.1039/a909457a

Synthesis, resolution and crystallographic characterization of a new
C2-symmetric planar-chiral bipyridine ligand: application to the catalytic
enantioselective cyclopropanation of olefins
Ramon Rios, Jack Liang, Michael M.-C. Lo and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
E-mail: gcf@mit.edu
Received (in Corvallis, OR, USA) 29th November 1999, Accepted 26th January 2000
The synthesis of a new C2-symmetric planar-chiral bipyr-
idine ligand is described, as well as its application to the
enantioselective CuI-catalyzed cyclopropanation of olefins.
The enantiomers of ligand 1 can be separated by chiral HPLC
(Regis Whelk-O column). We have established the absolute
configuration of (+)-1 through X-ray crystallography.
In order to validate our ligand design, we chose to investigate
the application of bipyridine 1 to the CuI-catalyzed cyclopropa-
nation of olefins, a reaction that has previously been used to
benchmark new chiral bipyridine designs.8 We were pleased to
observe that with the 2,6-di-tert-butyl-4-methylphenyl ester of
diazoacetic acid as the carbene source, we can cyclopropanate
an array of olefins with high stereoselectivity (Table 1). For
example, treatment of styrene with 1% CuOTf, 1.2% (+)-1, and
2 equiv. of diazo ester in CH2Cl2 at room temperature furnishes
the trans-cyclopropane in very good diastereomeric and
enantiomeric excess (94% de, 87% ee; Table 1, entry 1). The
stereoselection remains unchanged even at a very low catalyst
loading (0.25%), although the yield drops somewhat (60%). It is
worth noting that, in contrast to many previously reported CuI-
catalyzed cyclopropanations wherein the diazo ester is the
limiting reagent, our conditions employ the olefin as the
limiting reagent. Among the copper sources and the solvents
that we have examined, CuOTf and CH2Cl2 appear to be
optimal.
As Togni and Venanzi have recently documented, the use of
transition metal catalysts that employ nitrogen-donor ligands is
expanding rapidly.1 With respect to neutral, bidentate, nitrogen
donors, 2,2A-bipyridine is one of the most widely used.2,3 As a
consequence, the development of an effective chiral derivative
of bipyridine is a challenge of considerable importance.4,5 We
have recently been exploring the application of planar-chiral
heterocycles in asymmetric catalysis, both as enantioselective
nucleophilic catalysts6 and as chiral ligands for transition
metals.7 Here we describe our first investigation in the area of
chiral bipyridine chemistry, specifically, the synthesis, resolu-
tion and crystallographic characterization of C2-symmetric
planar-chiral ferrocene derivative 1. To benchmark this new
In the presence of CuOTf/1, we can effect the catalytic
enantioselective cyclopropanation of an array of olefins (Table
ligand, we have chosen to follow the lead of others by
examining its utility in the CuI-catalyzed cyclopropanation of
olefins [eqn. (1)].8–10
Our synthesis of ligand 1 begins with previously reported
pyridine derivative 2,11 which is available in one step from
commercially available materials (Scheme 1). Chlorination
with POCl3 affords compound 3 in 74% yield, and a standard
sequence of oxidation, acetoxylation and elimination then
furnishes pyrindine 6.6a The five-membered ring of 6 is
complexed to iron through reaction of its lithium salt with
(Cp*FeCl)n (59%),6a and the resulting ferrocene derivative is
then reductively coupled with NiBr2(PPh3)2/Zn/Et4NI,12
thereby providing racemic 1 as a single diastereomer in 58%
yield. This route is amenable to the synthesis of multi-gram
quantities of this new C2-symmetric, planar-chiral bipyridine
ligand.
Scheme 1 Reagents and conditions: i, POCl3, 74%; ii, H2O2, AcOH, 88%;
iii, Ac2O, 58%; iv, H2SO4, 79%; v, BuLi, then (Cp*FeCl)n, 58%; vi, 30%
NiBr2(PPh3)2, Zn, Et4NI, 58%.
DOI: 10.1039/a909457a
Chem. Commun., 2000, 377–378
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Table 1 Scope of the CuI/1-catalyzed enantioselective cyclopropanation of
olefinsa
plexes provides a wealth of opportunities for applications of
these ligands in asymmetric catalysis.
Support has been provided by the Alfred P. Sloan Founda-
tion, the American Cancer Society, Bristol-Myers Squibb, the
Camille and Henry Dreyfus Foundation, Merck, the National
Science Foundation, Novartis, Pfizer, Pharmacia & Upjohn,
Procter & Gamble, the Spanish Ministry of Education, and
Union Carbide.
Notes and references
† Crystal data for [Cu((R,R)-1)(PhCHNCH2)]PF6 (green): C46H52CuF6-
Fe2N2P, M = 953.11, orthorhombic, space group P212121, m = 1.315
mm21, a = 7.8830(16), b = 20.670 (4), c = 25.167(5) Å, V = 4100.8(14)
Å3, Z = 4, T = 183(2) K, 16506 reflections collected, 5878 independent
reflections (Rint = 0.1378), 518 variables, R = 0.0465, Rw = 0.0549 [I >
2s(I)], Flack parameter = 20.02(2). CCDC 182/1534.
1 A. Togni and L. M. Venanzi, Angew. Chem., Int. Ed. Engl., 1994, 33,
497.
2 F. Blau, Chem. Ber., 1888, 21, 1077.
3 J. Reedijk, in Comprehensive Coordination Chemistry, ed. G. Wilk-
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1). For styrene derivatives, we have made the interesting
observation that whereas the electronic nature of the aromatic
ring has only a modest effect on trans+cis diastereoselectivity,
it exerts a very significant impact on enantioselectivity (entries
1–3). Thus, reaction of electron-rich 4-methoxystyrene pro-
ceeds with relatively moderate ee (75%, entry 2), whereas
reaction of electron-poor 4-trifluoromethylstyrene occurs with
quite high ee (94%, entry 3). Alkyl-substituted olefins (entry 4)
and vinylsilanes (entry 5) undergo cyclopropanation with
excellent diastereoselectivity and good enantioselectivity.
An examination of the X-ray crystal structure of [Cu-
((2)-1)(styrene)]PF6† clearly shows that bidentate complexa-
tion of ligand 1 to copper furnishes a well-defined C2-
symmetric binding pocket [Fig. 1(a)]. The styrene is bound to
copper in an orientation that is predictable on the basis of
minimizing steric interactions with ligand 1 [Fig. 1(b)].
In summary, we have described the synthesis, resolution and
crystallographic characterization of a new class of C2-symmet-
ric planar-chiral bipyridine ligands, and we have demonstrated
the effectiveness of our ligand design through a study of CuI-
catalyzed cyclopropanations of olefins. The chiral environment
afforded by this family of bidentate ligands should be readily
tunable, both through a change in the metal fragment (e.g.
FeCp* ? FeC5Ph56b) and through the incorporation of
substituents in the 7 and 7A positions. The large number of
processes known to be catalyzed by bipyridine–metal com-
4 For a review, see: G. Chelucci, Gazz. Chim. Ital., 1992, 122, 89. See
also: C. Bolm, in Organic Synthesis via Organometallics, ed. K. H. Dötz
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Chem., Int. Ed. Engl., 1990, 29, 205; P. Collomb and A. von Zelewsky,
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D. O’Neill, B. Akermark and P. Helquist, J. Am. Chem. Soc., 1996, 118,
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Fig. 1 X-Ray crystal structure of [Cu((2)-1)(styrene)]PF6 (the non-
coordinating PF6 counter ion has been omitted for clarity): (a) without
styrene; (b) with styrene.
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Chem. Commun., 2000, 377–378