Autocatalytic Asymmetric Reduction of 2,6-Diacetylpyridine

Article abstract of DOI:10.1021/ol035515k

(Formula presented). We report here that the C₂-symmetric diol 2,6-bis(1-hydroxyethyl)pyridine (2) can effect chiral-catalyzed reduction of 2,6-diacetylpyridine (1) and produce more of the diol (2) with the same configuration in an enantiomerically enriched form. The two carbonyl functionalities of (1) are reduced in 90% conversion to produce the enantio-enriched C₂-symmetric diol (40% ee, 47% de) using zinc trifluoromethanesulfonate and a catalytic amount of the chiral C ₂-symmetric diol (2).

Full text of DOI:10.1021/ol035515k

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3947-3949
Autocatalytic Asymmetric Reduction of
2,6-Diacetylpyridine
Francis B. Panosyan and Jik Chin*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
M5S 3H6, Toronto, Canada
jchin@chem.utoronto.ca
Received August 11, 2003
ABSTRACT
We report here that the C -symmetric diol 2,6-bis(1-hydroxyethyl)pyridine (2) can effect chiral-catalyzed reduction of 2,6-diacetylpyridine (1)
2
and produce more of the diol (2) with the same configuration in an enantiomerically enriched form. The two carbonyl functionalities of (1) are
reduced in 90% conversion to produce the enantio-enriched C -symmetric diol (40% ee, 47% de) using zinc trifluoromethanesulfonate and a
2
catalytic amount of the chiral C -symmetric diol (2).
2
The first asymmetric example of an autocatalytic reaction
was reported by Soai and co-workers, whereby dialkylzinc
reagents were added to 3-pyridinecarboxyaldeyde to produce
the enantio-enriched pyridyl alkanol.1 This pioneering work
was further developed over the years to produce an excep-
tionally efficient autocatalytic system in the form of diiso-
propylzinc addition to 5-pyrimidinecarboxyaldehydes.2 Au-
tocatalytic asymmetric reactions continue to generate
considerable interest,3 and autocatalytic self-replication can
provide some valuable insight into replication reactions in
nature.4
(Table 1). To the best of our knowledge, this is the first
reported example of an autocatalytic asymmetric reduction.
The C2-symmetric diol (2) can be readily obtained, in high
enantiomeric purity, through reduction of 2,6-diacetylpyridine
(1) using stoichiometric amounts of chiral DIP-Cl.5 Alter-
natively, the diol 2 can be produced by catalytic asymmetric
hydrogenation of 2,6-diacetylpyridine 1.6 The diol (2) has
been shown to be a useful intermediate in the synthesis of
other chiral ligands.7 It has also been examined as a chiral
ligand for the enantioselective addition of diethylzinc to
aldehydes.8
In our efforts to effect catalytic asymmetric reduction of
2,6-diacetylpyridine (1) using a chiral Zn(II) complex as a
Lewis acid, we have discovered that the product of the
reaction itself (2) can catalyze stereoselective reduction of
1 and produce more of the diol 2 with the same configuration
(3) (a) Buono, F. G.; Blackmond, D. G. J. Am. Chem. Soc. 2003, 125,
8978. (b) Todd, M. H. Chem. Soc. ReV. 2002, 31, 211. (c) Singleton, D.
A.; Vo, L. K. J. Am. Chem. Soc. 2002, 124, 10010. (d) Blackmond, D. G.;
McMillan, C. R.; Ramdeehul, S.; Schorm, A.; Brown, J. M. J. Am. Chem.
Soc. 2001, 123, 10103. (e) Feringa, B. L.; van Delden, R. A. Angew. Chem.,
Int. Ed. 1999, 38, 3419. (f) Bolm, C.; Bienewald, F.; Seger, A. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1657. (g) Alberts, A. H.; Wynberg, H. J.
Am. Chem. Soc. 1989, 111, 7265.
(1) Soai, K.; Niwa, S.; Hori, H. J. Chem. Soc., Chem. Commun. 1990,
982.
(4) (a) Siegel, J. S. Nature 2002, 419, 346. (b) Saghatelian, A.;
Yokobayashi, Y.; Soltani, K.; Ghadiri, M. R. Nature 2001, 409, 797. (c)
Bada, J. L. Nature 1995, 374, 594.
(5) (a) Ramachandran, P. V.; Chen, G. M.; Lu, Z. H.; Brown, H. C.
Tetrahedron Lett. 1996, 37, 3795. (b) Ramachandran, P. V.; Teodorovic,
A. V.; Rangaishenvi, M. V.; Brown, H. C. J. Org. Chem. 1992, 57, 2379.
(c) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am. Chem.
Soc. 1988, 110, 1539. In our hands, the reduction of 2,6-diacetylpyridine 1
with (+)-DIP-Cl afforded the (R,R)-diol 2 in 82% yield with 95% ee and
78% de.
(2) (a) Sato, I.; Urabe, H.; Ishiguro, S.; Shibata, T.; Soai, K. Angew.
Chem., Int. Ed. 2003, 42, 315. (b) Soai, K.; Shibata, T.; Sato, I. Acc. Chem.
Res. 2000, 33, 382. (c) Shibata, T.; Yamamoto, J.; Matsumoto, N.;
Yonekubo, S.; Osanai, S.; Soai, K. J. Am. Chem. Soc. 1998, 120, 12157.
(d) Shibata, T.; Morioka, H.; Hayase, T.; Choji, K.; Soai, K. J. Am. Chem.
Soc. 1996, 118, 471. (e) Soai, K.; Shibata, T.; Morioka, H.; Choji, K. Nature
1995, 378, 767. (f) Shibata, T.; Yonekubo, S.; Soai, K. Angew. Chem., Int.
Ed. 1999, 38, 659.
10.1021/ol035515k CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/25/2003

Table 1. Effect of Catalyst Loading on Autocatalytic
Reduction of 2,6-Diacetylpyridine 1
entrya
2a (mol %)
Zn(OTf)2 (mol %)
eeb (%)
deb (%)
1
2
3
4
5
0
0
10
20
20
10
20
5
10
120
0
0
28
38
40
35
45
25
41
47
a Conversions were determined by 1H NMR and were >80% after 24 h.
b Ee and de were determined by chiral HPLC on a Chiralcel OD-H column
and corrected for the added diol 2.
Figure 1. Effect of additives on the reduction of 2,6-diacetylpy-
ridine with sodium triacetoxyborohydride in the presence of
stoichiometric amounts of zinc trifluoromethanesulfonate in dichlo-
1
romethane. Conversions were determined by H NMR after 24 h.
In a typical reduction experiment, 2,6-diacetylpyridine (1)
(10 mM) was treated with sodium triacetoxyborohydride (20
mM), p-nitrophenol (PNP) (60 mM), (R,R)-2 (20 mol %),
and zinc trifluoromethanesulfonate and stirred for 24 h at
room temperature. The double reduction proceeded to 90%
conversion in dichloromethane, and the diol (2) obtained after
basic workup was determined by chiral HPLC to be
enantiomerically enriched in the (R,R) form (40% ee and
47% de, Table 1, entry 5). The % conversion, ee, and de
were corrected for the added diol 2.
Interestingly, diastereoselectivity was observed even with-
out addition of the chiral diol. When 1 was reduced in the
presence of catalytic amounts of zinc trifluoromethane-
sulfonate, diol 2 was produced in a diastereomerically
enriched form, where the homochiral form ((R,R)- and (S,S)-)
of the diol predominates, but no enantiomeric excess was
observed (Table 1, entries 1 and 2). The amount of zinc in
the system can be reduced to catalytic amounts without
significant change in selectivity (Table 1, entry 4), perhaps
due to the poor solubility of the free zinc in dichloromethane.
The reducing system used in this reaction is generated in
situ by a novel combination of sodium triacetoxyborohydride
and p-nitrophenol. A variety of additives with acidic protons
were investigated for the reduction of 2,6-diacetylpyridine
1, and p-nitrophenol was found to be the most effective
(Figure 1).
(PhOH, phenol; HFP, 1,1,1,3,3,3-hexafluoro-2-propanol; PNP,
p-nitrophenol; PhSH, thiophenol; PFP, pentafluorophenol).
system is insensitive to the presence of aromatic rings but is
affected by the acidity of the additive.
p-Nitrophenol reacts with sodium triacetoxyborohydride
to produce tris(p-nitrophenoxy)borohydride 3 (eq 1). The
complete substitution of the acetate groups with p-nitrophe-
noxy (OPNP) groups to produce the new borohydride species
1
3 is evident through H NMR, where the acetate signal at
1.99 ppm is replaced by the acetic acid signal at 2.08 ppm
after only 5 min at room temperature in dichloromethane
(see Supporting Information). The 11B NMR spectral analysis
in methanol indicates the presence of a single species at (δ
18.6). Alcohols with enhanced acidity have been shown to
react with sodium borohydride to generate tris(alkoxy)-
borohydrides.9 In contrast to the well-known disproportion-
ation of alkoxyborohydrides, these tris(alkoxy)borohydrides,
formed from acidic alcohols, are quite stable and resistant
to any disproportionation.
The reduction worked in the presence of other proton
sources. Thiophenol (PhSH) was found to be only slightly
less effective than p-nitrophenol. The reduction was less
effective with additives such as pentafluorophenol (PFP),
1,1,1,3,3,3-hexafluoro-2-propanol (HFP), and phenol (PhOH).
1,1,1,3,3,3-Hexafluoro-2-propanol (HFP) was just as effec-
tive as phenol (PhOH), which leads us to believe that the
In the absence of p-nitrophenol, no appreciable enantio-
selectivity was observed; therefore, we believe 3 to be
important for the construction of the proposed active catalyst
4 (Scheme 1).
Molecular mechanics computation10 of 1 coordinated to
the proposed active catalyst (R,R)-4 shows that the two Re-
faces of 1 are blocked by the tris-(alkoxy)borohydride groups
of 4 (see Supporting Information for a graphic illustration).
(6) Ohkuma, T.; Koizumi, M.; Yoshida, M.; Noyori, R. Org. Lett. 2000,
2, 1749.
(7) (a) Chen, G. M.; Brown, H. C.; Ramachandran, P. V. J. Org. Chem.
1999, 64, 721. (b) Sablong, R.; Osborn, J. A. Tetrahedron Lett. 1996, 37,
4937. (c) Jiang, Q. Z.; VanPlew, D.; Murtuza, S.; Zhang, X. M. Tetrahedron
Lett. 1996, 37, 797.
(9) Golden, J. H.; Schreier, C.; Singaram, B.; Williamson, S. M. Inorg.
Chem. 1992, 31, 1533.
(8) (a) Le Goanvic, D.; Holler, M.; Pale, P. Tetrahedron: Asymmetry
2002, 13, 119. (b) Brown, H. C.; Chen, G. M.; Ramachandran, P. V.
Chirality 1997, 9, 506.
(10) Molecular mechanics computation was performed using HyperChem
5.0 from HyperCube, Inc., Gainesville, Florida. Octahedral geometry was
assumed for the Zn(II) complex.
3948
Org. Lett., Vol. 5, No. 21, 2003

Scheme 1. Proposed Catalytic Rationale
Figure 2. 1H NMR of 2 in d4-methanol. The doublet represents
the -CH3 of the diol. (a) Compound 2. (b) 2-zinc complex. (c)
2-zinc complex after reaction with NaBH(OPNP)3 3.
reaction employs a novel reducing system, which is generated
in situ from sodium triacetoxyborohydride and p-nitrophenol.
Detailed mechanistic studies of the described system are
ongoing.
The active catalyst 4 is only slightly soluble in dichlo-
romethane, and the system operates under heterogeneous
conditions. The 1H NMR data obtained through an investiga-
tion of the system in a homogeneous medium (Figure 2)
indicates that an initial coordination of the diol 2 to zinc is
followed by the reaction to borohydride 3 to form the
proposed active species 4. The reaction to borohydride 3 is
assisted by zinc, which increases the acidity of the diol in
complex 4.
In summary, we have described a new autocatalytic
asymmetric system that generates two chiral centers through
the reduction of 2,6-diacetylpyridine. The C2-symmetric diol
2 was shown to interact with the metal and the reducing agent
to produce what is believed to be the active catalyst 4. The
Acknowledgment. We thank the Natural Sciences and
Engineering Council of Canada for financial support of this
work. F.B.P acknowledges the receipt of a University of
Toronto Fellowship.
Supporting Information Available: Detailed experi-
1
mental procedures, including H and 11B NMR spectra,
HPLC analysis of compound 2, and a graphic representation
of the modeled active complex. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL035515K
Org. Lett., Vol. 5, No. 21, 2003
3949