Synthesis of a new chiral nonracemic C2-symmetric 2,2′-bipyridyl ligand and its application in copper(I)-catalyzed enantioselective cyclopropanation reactions

Article abstract of DOI:10.1021/ol049853c

An efficient synthesis of a low molecular weight, chiral nonracemic and (C₂-symmetric bipyridyl ligand is reported. The ligand was prepared using a catalytic asymmetric dihydroxylation reaction of a pyrindine as a key step. The ligand was evalu

Full text of DOI:10.1021/ol049853c

ORGANIC
LETTERS
2004
Vol. 6, No. 5
855-857
Synthesis of a New Chiral Nonracemic
C -Symmetric 2,2′-Bipyridyl Ligand and
2
Its Application in Copper(I)-Catalyzed
Enantioselective Cyclopropanation
Reactions
Michael P. A. Lyle and Peter D. Wilson*
Department of Chemistry, Simon Fraser UniVersity, 8888 UniVersity DriVe, Burnaby,
British Columbia, Canada V5A 1S6
pwilson@sfu.ca
Received January 26, 2004
ABSTRACT
An efficient synthesis of a low molecular weight, chiral nonracemic and C -symmetric bipyridyl ligand is reported. The ligand was prepared
2
using a catalytic asymmetric dihydroxylation reaction of a pyrindine as a key step. The ligand was evaluated in the asymmetric copper(I)-
catalyzed cyclopropanation reactions of a series of alkenes and diazoesters. Very high diastereoselectivities and enantioselectivities were
observed (>95:5 dr and up to 99% ee). These are the highest reported stereoselectivities for a chiral bipyridyl ligand.
Of the many types of chiral ligands that have been developed
for catalytic asymmetric synthesis, chiral nonracemic 2,2′-
bipyridines and 1,10-phenanthrolines have received consider-
able recent attention.1,2 The 2,2′-bipyridine unit offers the
potential for a broad range of structural modifications that
include the incorporation of stereogenic centers as well as
elements of planar and axial chirality.1 In addition, the
electronic properties of this type of ligand may be adjusted
by appropriate functionalization of the pyridine moieties.
This class of bidentate ligand complements the prominent
class of chiral ligands, the bis(oxazolines) that have been
employed to a great degree of success in many asymmetric
transformations.3 In this paper, we report an efficient
synthesis of the low molecular weight, chiral nonracemic
and C2-symmetric bipyridyl ligand (+)-1 (Figure 1). The
asymmetry of this novel chiral ligand was installed by the
use of a catalytic asymmetric reaction that negated the use
of chiral pool starting materials or resolution procedures. The
evaluation of this chiral ligand as a highly effective chiral
director in the asymmetric copper(I)-catalyzed cyclopropa-
nation reactions of a series of alkenes and diazoesters is also
described.
(1) (a) Malkov, A. V.; Kocˇovsky´, P. Curr. Org. Chem. 2003, 7, 1737.
(b) Chelucci, G.; Thummel, R. P. Chem. ReV. 2002, 102, 3129. (c) Fletcher,
N. C. J. Chem. Soc., Perkin Trans. 1 2002, 1831.
(2) For discussions on the coordination chemistry of 2,2′-bipyridines and
1,10-phenanthrolines, see: (a) Reedijk, J. In ComprehensiVe Coordination
Chemistry; Wilkinson, G., Gillard, R. D., McCleverty, J. A., Eds.; Pergamon
Press: Oxford, 1987; Vol. 2, pp 73-98. (b) Kaes, C.; Katz, A.; Hosseini,
M. W. Chem. ReV. 2000, 100, 3553.
(3) For a recent review on chiral bis(oxazolines) in asymmetric transition
metal catalyzed reactions, see for example: (a) Johnson, J. S.; Evans, D.
A. Acc. Chem. Res. 2000, 33, 325.
10.1021/ol049853c CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/11/2004

the pyrindine 5 with AD-mix-â afforded the diol (+)-6
(assigned 6S,7R stereochemistry), which on subsequent
condensation with 3-pentanone afforded the acetal (+)-7 in
reasonable overall yield (57%) and in very high enantiomeric
excess (90%).8,9 To the best of our knowledge, this is the
highest reported catalytic AD reaction of a cyclic cis-
alkene.10,11 The absolute stereochemistry of the diol (+)-6
has not yet been determined definitively but was assigned
on the basis of the well-established predictability of the
Sharpless AD reaction and the sense of the following
asymmetric cyclopropanation (AC) reactions.1,8 Repeating
the above two-step procedure with AD-mix-R afforded the
acetal (-)-7 in 48% yield and in 82% ee. To improve the
yield and rate of the AD reaction, it was modified and
performed with 1 mol % of potassium osmate dihydrate and
5 mol % of the chiral ligand (DHQD)2PHAL.12 This afforded
the corresponding acetal (+)-7 in 81% overall yield and in
90% ee. The rate of the AD reaction was also significantly
improved. Employing N-methylmorpholine-N-oxide in place
of potassium ferricyanide, as the stoichiometric oxidant in
the latter two-step procedure, afforded the acetal (+)-7 in
89% overall yield.13 However, the required reaction time was
longer, and the enantioselectivity of this AD reaction was
significantly compromised (61% ee).
Figure 1. Chiral nonracemic C2-symmetric 2,2′-bipyridyl ligand
(+)-1.
The synthesis of the bipyridyl ligand (+)-1 began from
the 2-hydroxypyridine (pyridinone) 2, which can be prepared
on a multigram scale from cyclopentanone and ethyl ac-
etoacetate (Scheme 1).4 This compound was converted to
Scheme 1. Synthesis of 2,2′-Bipyridyl Ligand (+)-1a
The new chiral nonracemic and C2-symmetric 2,2′-
bipyridyl ligand (+)-1 was prepared by a nickel-mediated
coupling reaction of the acetal (+)-7 in 84% yield.14 A small
amount of the corresponding meso-bipyridine was also
isolated from this reaction by flash chromatography (∼5%).
The enantiomeric purity of the bipyridyl ligand (+)-1 was
determined by analytical chiral HPLC and found to be greater
than 99% ee. This indicated that significant enrichment of
the enantiomeric purity of the chiral material had occurred
in this coupling reaction. The enantiomeric bipyridyl ligand
(-)-1 was prepared accordingly in 53% yield (unoptimized)
and was also found to have an enantiomeric excess that was
greater than 99%.
a Reagents and conditions: (a) ethyl acetoacetate, NH4OAc (ref
4); (b) PhP(O)Cl2, 160 °C, 16 h, 83%; (c) H2O2, H2O, AcOH, 80
°C, 16 h; (d) Ac2O, rt, 1 h then 100 °C, 4 h, 60% (over two steps);
(e) H2SO4, 120 °C, 10 min, 81%; (f) AD-mix-â, t-BuOH/H2O (1:
1), 0 °C, 12 h or 1 mol % K2OsO4‚2H2O, 5 mol % (DHQD)2PHAL,
K3Fe(CN)6, K2CO3, t-BuOH/H2O (1:1), 0 °C, 2 h; (g) 3-pentanone,
PhH, p-TsOH (cat.), reflux, 16 h, 57% and 81%, respectively
(over two steps); (h) NiCl2(H2O)6, PPh3, Zn, DMF, 60 °C, 4 h,
84%.
(8) For a review on AD reactions, see: Kolb, H. C.; VanNieuwenhze,
M. S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483.
(9) The enantioselectivity of this AD reaction was determined by
analytical chiral HPLC (Daicel Chiracel OD column).
(10) For comparison, AD of indene with AD-mix-â affords the corre-
sponding diol (6S,7R stereochemistry) in 33-40% ee; see: Spivey, A. C.;
Hanson, R.; Scorah, N.; Thorpe, S. J. J. Chem. Ed. 1999, 76, 655. Hanessian
and co-workers have reported that indene can be dihydroxylated with
a simple C2-symmetric chiral ligand derived from (1R,2R)-trans-1,2-
diaminocyclohexane in 80% ee (70% yield). However, the chiral ligand
and osmium tetroxide are used stoichiometrically in this reaction; see:
Hanessian, S.; Meffre, P.; Girard, M.; Beaudoin, S.; Sance´au, J.-Y.; Bennani,
Y. J. Org. Chem. 1993, 58, 1991.
the 2-chloropyridine 3 on heating with phenylphosphonic
dichloride.5,6 Subsequent oxidation with hydrogen peroxide
afforded the corresponding pyridine N-oxide, which was
converted to the acetate 4 on heating with acetic anhydride.
The pyrindine 5 was prepared, as a single regioisomeric
product (>30:1), on briefly heating the acetate 4 in concen-
trated sulfuric acid.7 Asymmetric dihydroxylation (AD) of
(11) Interestingly, the overall yield of the corresponding quinoline
derivative of the acetal (+)-7 that has been prepared from cyclohexanone
by the same procedures was significantly greater. However, the enantiomeric
purity of this acetal was poor (∼5% ee).
(12) The rate and yield of this process was not improved by the addition
of methanesulfonamide. Sharpless and co-workers have reported an
improvement in the rate of the AD reaction of indene with the chiral ligand
(DHQD)2PHAL using methanesulfonamide as an additive and 1 mol % of
potassium osmate dihydrate: (a) Wang, Z.-M.; Kakiuchi, K., Sharpless, K.
B. J. Org. Chem. 1994, 59, 6895. (b) Wang, L.; Sharpless, K. B. J. Am.
Chem. Soc. 1992, 114, 7568.
(4) Sakurai, A.; Midorikawa, H. Bull. Chem. Soc. Jpn. 1968, 41, 165.
(5) Rios, R.; Liang, J.; Lo, M. M.-C.; Fu, G. C. Chem. Commun. 2000,
377.
(6) Robison, M. M. J. Am. Chem. Soc. 1958, 80, 6254.
(7) On heating the acetate 4 with concentrated sulfuric acid for an
extended period of time (1 h) the regioselectivity of this elimination reaction
was compromised (9:1). Ruble and Fu have reported a related example in
which a functionalized pyrindine is formed as a mixture of regioisomers
(2:1): Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230 (Supporting
Information).
(13) Wang, Z.-M.; Sharpless, K. B. J. Org. Chem. 1994, 59, 8302.
(14) (a) Dehmlow, E. V.; Sleegers, A. Liebigs Ann. Chem. 1992, 953.
(b) Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.; Oda, M. Bull. Chem. Soc.
Jpn. 1990, 63, 80.
856
Org. Lett., Vol. 6, No. 5, 2004

observed reproducibility of these AC reactions. It is known
that the enantioselectivity of AC reactions of styrene deriva-
tives with bipyridyl complexes are susceptible to electronic
effects.5,19 It was found that the AC reaction of electron-
rich p-methoxystyrene 8b afforded cyclopropane 10d in
moderate enantiomeric excess (71%). However, the electron-
poor p-fluorostyrene 8c afforded cyclopropane 10e in
exceptionally high enantiomeric excess (99%). The latter
result is, to the best of our knowledge, the highest reported
enantioselectivity for an AC reaction with a chiral bipyridyl
ligand. The ligand (+)-1 was also used to cyclopropanate a
terminal alkene, 4-phenyl-1-butene 8d, and a 1,1-disubsti-
tuted alkene, 1,1-diphenylethene 8e, in good to moderate
enantiomeric excess.19,20
The stereochemical outcome of these AC reactions can
be rationalized in terms of minimization of steric interactions
between the reacting species and the copper(I) complex of
the bipyridyl ligand (+)-1.19,21 The high enantioselectivities
can be rationalized in terms of the structural rigidification
that is provided by the chiral acetal moieties of the C2-
symmetric bipyridyl ligand.22
Table 1. Asymmetric Cyclopropanation of Alkenes 8a-e
yield
eec
entry L*
R1
R2 R3 product trans:cisa (%)b (trans)
1
2
3
4
5
6
7
8
(+)-1 Ph
H
H
H
H
H
H
H
Et
10a
80:20
92:8
93:7
92:8
>95:5
92:8
74
49
67
68
69
73
82
81
82
84
92
93d
71
99
83
72
(+)-1 Ph
(+)-1 Ph
(-)-1 Ph
Bn 10b
t-Bu 10c
t-Bu ent-10c
t-Bu 10d
t-Bu 10e
t-Bu 10f
(+)-1 p-MeOC6H4
(+)-1 p-FC6H4
(+)-1 PhCH2CH2
(+)-1 Ph
>95:5
Ph t-Bu 10g
1
a Determined by analysis of the H NMR spectra of the crude reaction
products. b Combined yield of chromatographically separated trans- and cis-
cyclopropanes. c Determined by analytical chiral HPLC (Daicel Chiracel
OD column) following reduction to the corresponding primary alcohols with
lithium aluminum hydride. The reactions were also performed in the absence
of the chiral ligand to provide reference samples for these analytical
measurements. d The product is the enantiomer of that indicated in the
reaction scheme.
In conclusion, an efficient synthesis of a low molecular
weight, chiral nonracemic and C2-symmetric 2,2′-bipyridyl
ligand (+)-1 has been achieved from readily available starting
materials. The chirality of the ligand was installed by an
enantioselective catalytic AD reaction. This ligand was found
to be highly effective in the AC reactions of a variety of
alkenes with tert-butyl diazoacetate 9c. Very high diaste-
reoselectivities (>95:5) and enantioselectivities (99% ee)
were observed. Current investigations are focused on the use
of the bipyridyl ligand (+)-1 in other catalytic asymmetric
processes and on the preparation of derivatives of this ligand
by condensation of the diol (+)-6 with a variety of sym-
metrical ketones.
The bipyridine (+)-1 was evaluated as a chiral ligand for
use in catalytic asymmetric synthesis by undertaking a series
of copper(I)-catalyzed AC reactions (Table 1).15
The active copper(I)-catalyst was generated by reduction
of the complex formed between 1.25 mol % of copper(II)
triflate and 1.50 mol % of the ligand (+)-1 with phenylhy-
drazine. The AC reactions were carried out at room tem-
perature in dichloromethane and involved the slow addition
of the diazoesters 9a-c (over ∼3 h) to a solution of alkenes
8a-e and the preformed catalyst according to standard
procedures.16 Of note, the diazoesters 9a-c were employed
as the limiting reagent. The AC reaction of styrene 8a with
ethyl diazoacetate 9a afforded the cyclopropane 10a in good
yield, diastereoselectivity and enantioselectivity.1,17 This
result compares favorably with several other known chiral
2,2′-bipyridyl ligands.1 Improved diastereoselectivity of this
reaction was observed when benzyl and tert-butyl diazoac-
etate 9b-c were used to prepare the corresponding cyclo-
propanes 10b-c.1,17,18 Very high enantioselectivity was also
recorded for the reaction of styrene 8a with tert-butyl
diazoacetate 9c.1,17 The enantiomeric ligand (-)-1 was used
to prepare cyclopropane ent-10c, which also illustrates the
Acknowledgment. We are grateful to the Natural Sci-
ences and Engineering Research Council of Canada (NSERC)
and Simon Fraser University for financial support. M.P.A.L.
thanks Simon Fraser University for graduate research fel-
lowships and an entrance scholarship.
Supporting Information Available: Detailed experi-
mental procedures and product characterization data for all
of the compounds synthesized and 1H and 13C NMR spectra
for compounds (+)-1, 2-5 and (+)-7. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL049853C
(15) (a) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911. (b) Doyle,
M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919.
(16) For example, see: Malkov, A. V.; Pernazza, D.; Bell, M.; Bella,
M.; Massa, A.; Teply´, F.; Meghani, P.; Kocˇovsky´, P. J. Org. Chem. 2003,
68, 4727.
(17) The absolute stereochemistry of cyclopropane 10a was assigned as
1R,2R by comparison of the optical rotation with literature values; see for
example: Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. AdV. Synth. Catal.
2001, 343, 79 and references therein.
(19) Ito, K.; Katsuki, T. Tetrahedron Lett. 1993, 34, 2661.
(20) Bedekar, A. V.; Koroleva, E. B.; Andersson, P. G. J. Org. Chem.
1997, 62, 2518.
(21) (a) Ito, K.; Yoshitake, M.; Katsuki, T. Tetrahedron 1996, 52, 3905.
(b) Ito, K.; Katsuki, T. Chem. Lett. 1994, 1857.
(22) Of note, disubstituted chiral bis(oxazoline) ligands provide improved
enantioselection in AC reactions; see: Doyle, M. P. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter
5.
(18) Vallgårda, J.; Hacksell, U. Tetrahedron Lett. 1991, 32, 5625.
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