Enantioselective synthesis of planar-chiral ferrocene-fused 4-pyridones and their application in construction of pyridine-based organocatalyst library

Article abstract of DOI:10.1021/acs.orglett.5b01044

A couple of planar-chiral ferrocene-fused 4-pyridone derivatives 2a and 2b were synthesized in enantiomerically pure form by scalable asymmetric transformations. Pyridones 2 are versatile precursors to various ferrocene-fused pyridine derivatives, which a

Full text of DOI:10.1021/acs.orglett.5b01044

Letter
pubs.acs.org/OrgLett
Enantioselective Synthesis of Planar-Chiral Ferrocene-Fused
4‑Pyridones and Their Application in Construction of Pyridine-Based
Organocatalyst Library
Masamichi Ogasawara,*,† Shiro Wada,‡ Erika Isshiki,† Takumi Kamimura,‡ Akira Yanagisawa,*,‡
Tamotsu Takahashi,*,† and Kazuhiro Yoshida*,‡
†Catalysis Research Center and Graduate School of Life Science, Hokkaido University, Kita-ku, Sapporo 001-0021, Japan
‡Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
S
* Supporting Information
ABSTRACT: A couple of planar-chiral ferrocene-fused 4-pyridone derivatives 2a and 2b were synthesized in enantiomerically
pure form by scalable asymmetric transformations. Pyridones 2 are versatile precursors to various ferrocene-fused pyridine
derivatives, which are useful nucleophilic asymmetric organocatalysts.
erivatives of 4-dialkylaminopyridine (DAAP) are widely
utilized nucleophilic catalysts in various organic trans-
derivative of 1 with a different 4-substituent needs to be prepared
as a respective racemate through the independent reaction
sequence, and naturally, the last stage chiral resolution of each
compound is inevitable.
In this letter, we report the enantioselective synthesis of
planar-chiral 4-pyridones 2. Compounds 2, which were obtained
in enantiomerically pure form in multigram scales, are excellent
and versatile precursors to 1. The newly developed detosylative
amination of 2 provided diverse 1, including previously
unreported species, as single-enantiomers. Thus, the library of
the planar-chiral nucleophilic organocatalysts could be effectively
constructed.
D
formations.1 Their application in asymmetric synthesis has been
a recent trend and many efforts have been made to develop
effective chiral variants of DAAPs.2,3 Arguably the most
successful chiral DAAPs reported so far are planar-chiral
ferrocene-fused pyridine derivatives 1, which have been
developed by G. C. Fu since 1996.4,5 Although compounds 1
have showed excellent enantioselectivity in a wide range of
asymmetric reactions,4,5 applications of these elegant molecules
have been rather limited6 probably due to the complicated
synthesis (Scheme 1). Two apparent drawbacks in Fu’s synthetic
Our strategy for asymmetric synthesis of 1 consists of three key
steps: (i) introduction of proper substituents at the 1- and 2-
positions of a ferrocene platform with controlling its planar-
chirality, (ii) construction of a six-membered N-heterocycle by a
ring-closure reaction, and (iii) aromatization of the N-hetero-
cycle into a pyridine ring with introduction of a proper
substituent at the 4-position (Scheme 2, top).
Scheme 1. Reported Fu’s Original Synthesis of Planar-Chiral
Ferrocene-Fused 4-Dialkylaminopyridines 1
To realize the idea, planar-chiral pyridones 2 were designed as
versatile precursors to 1 (Scheme 2, bottom). Pyridones 2
possess a modifiable carbonyl group at the proper position, and
the last-stage introduction of a 4-amino group would make our
synthesis flexible, and thus, construction of the library of 1 might
be realized. Olefin metathesis was chosen for the cyclization step
since we have experienced utilizing RCM for construction of
protocols are (i) necessity of the last stage chiral resolution of
preformed racemic 1,4b,c,7 and (ii) limited diversity with respect
to a substituent at the 4-position in the pyridine ring. An amino
group at the 4-pyridyl position, which plays important roles in
controlling the activity/selectivity of DAAPs,8 was introduced in
the middle stage of the synthetic sequences. This means that each
Received: April 10, 2015
Published: April 20, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b01044
Org. Lett. 2015, 17, 2286−2289

Organic Letters
Letter
was carried out as above, and (S)-7b was isolated as deep-red
solid as a mixture of (E)- and (Z)-isomers (E/Z = 5/2).
Scheme 2. Strategy for Asymmetric Synthesis of Planar-Chiral
Ferrocene-Fused 4-Dialkylaminopyridines 1
Next, the ring-closing metathesis reactions of (S)-7a/7b were
examined. The two olefin moieties in (S)-7 are an electron
deficient enone and a nitrogen-bound internal olefin, which are
unfavorable situations for facile RCM. The Hoveyda/Grubbs-II
catalyst16 was a catalyst of choice for the RCM. After optimizing
the conditions, (S)-2a and (S)-2b were obtained both in 72%
yields (Scheme 4; see Supporting Information for details). The
Scheme 4. Ring-Closing Metathesis of (S)-7 Forming (S)-2
aromatic compounds9,10 as well as for modification of various
ferrocene substrates.11
At the outset, the synthesis of 2a that is with a CpFe moiety
was examined. Kagan’s acetal (−)-3a12 was converted to (−)-4a
in >98% de as reported.13 Tosylation and allylation of (−)-4a
afforded amide (+)-5a in 91% yield as a single diastereomer after
chromatographic purification. Deprotection of the chiral acetal
moiety followed by the Ru-catalyzed olefin isomerization14 gives
enamide (S)-6a in 97% yield as a mixture of (E)- and (Z)-isomers
(E/Z = 10/3). The formyl group in (S)-6a was transformed to an
acroyl group by the sequential vinylation/oxidation, and (S)-7a,
which was a RCM substrate, was obtained in 78% yield with
retention of enantiomeric homogeneity with respect to the
planar-chirality. Although (S)-7a was an inseparable mixture of
the (E)- and (Z)-isomers, this was not a drawback because the
RCM of both (E)- and (Z)-7a would lead to the same product
(2a) with elimination of propene (Scheme 3).
present protocol for preparing (S)-2 is scalable, and synthesis of
(S)-2b on a multigram scale was accomplished without any
difficulties.
Single crystals of (−)-2b were grown from pentane/
dichloromethane as deep red plates. The X-ray crystallography
revealed that the compound was single enantiomeric, and the
absolute configuration of (−)-2b was determined to be (S),
which is consistent with the stereochemistry reported on the
diastereoselective lithiation of (−)-3b (Figure 1, see Supporting
Information for details).12,15
Scheme 3. Enantio-/Diastereoselective Synthesis of Planar-
Chiral Ferrocene-Fused Enone-Enamide Derivatives (S)-7
Figure 1. Ball-and-stick drawing of the single-crystal X-ray structure of
(S)-(−)-2b with selected atom numbering.
Planar-chiral (S)-2a/2b were versatile precursors to various
pyridine derivatives (Scheme 5). Treatment of (S)-2a/2b with a
mixture of oxalyl chloride and DMF gave the corresponding 4-
chloropyridine derivatives (S)-8a or (S)-8b in 76% or 62% yields,
respectively.17 The C−Cl moiety in (S)-8 could be modified by
the palladium-catalyzed reactions. For example, the Buchwald−
Hartwig amination of (S)-8a with pyrrolidine afforded (S)-1av in
32% yield.18 The preparation of rac-8b and its conversion to 4-
methylpyridine derivative rac-9b via the Suzuki−Miyaura
coupling reaction (94% yield) were described previously.19
However, rac-9b needed to be resolved into the two enantiomers
using the chiral HPLC prior to its catalytic application. The same
reaction starting with single-enantiomeric (S)-8b should allow us
direct access to enantiomerically pure (S)-9b.
The synthesis of Cp* analogue (S)-7b could be achieved in a
similar manner with slight modifications. Chiral acetal (−)-3b15
was converted to 4b via diastereoselective azidation and the Pd-
catalyzed hydrogenation. With the more electron-donating Cp*
ligand, aminoferrocene 4b is more susceptible to air-oxidation,
and thus, crude 4b was converted to (+)-5b without purification.
The NMR analysis of (+)-5b showed the isolated sample being
single-diastereomeric. The transformation of (+)-5b into (S)-7b
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Organic Letters
Letter
Scheme 5. Conversion of Pyridones 2 to Pyridine Derivatives
Table 1. Enantioselective Addition of o-tBu-Phenol to
Ethyl(p-tolyl)ketene Catalyzed by (S)-1
a
b
c
entry
(S)-1
yield (%)
% ee
1
2
3
4
5
6
7
8
9
1au
1av
1aw
1bu
1bv
1bw
1bx
1by
1bz
89
88
57
92
90
84
90
92
89
52
57
12
79
92
79
90
88
87
a
The reaction was carried out in toluene at 23 °C in the presence of
catalyst (S)-1 (3 mol %). The absolute configuration of 14 was
b
deduced by comparison with the reported results [ref 4i]. Isolated
c
yield by silica gel chromatography. Determined by HPLC analysis on
a chiral stationary phase (see the Supporting Information for details).
92% ee (entries 4−9). Among the library of the pyridine
organocatalysts prepared, those with the pyrrolidyl (1bv) or the
diethylamino (1bx) substituent afforded (R)-14 in greater than
90% ee (entries 5 and 7).
The second asymmetric reaction examined is the kinetic
resolution of racemic alcohol 15.4b The acetylation of rac-15 with
acetic anhydride proceeds in an enantioselective fashion in the
presence of (S)-1 (4 mol %) to give ester (S)-16 and recovered
(R)-15 (Table 2). All the ferroco-pyridines (1bu−1by) showed
The direct conversion of 2 into various DAAP derivatives (S)-
1 was achieved by the reaction with an appropriate N-
trimethylsilylamine in the presence of titanium tetrachloride in
good yields.20 For the detosylative amination reaction, two
equivalents of N-silylamine were required. The process most
likely proceeded via an initial formation of iminium species 10,
which also existed in different resonance form 11. The
subsequent reaction of N-tosylpyridinium 11 with R2NSiMe3
afforded the corresponding 1 together with tosylamide TsNR2,
which was indeed isolated from the reaction mixture. DMAP
(1au, 1bu), PPY (1av, 1bv), morpholyl (1aw, 1bw), and
diethylamino (1bx) derivatives were prepared in good to
excellent yields by the reaction using the corresponding
commercial silylamines. The silylamine species generated in
situ from isoindoline, iPrMgBr, and Me3SiCl could be used for
the present reaction as well, and 1by was obtained in 39% yield.
The detosylative amination of (S)-2b could be operative without
using silylamines, and the combination of N-benzylmethylamine,
TiCl4, and DBU furnished (S)-1bz, which is with the
unsymmetric 4-dialkylamino substituent, in 37% yield. It should
be emphasized that all the transformations shown in Scheme 5
are enantioretentive. Whereas (S)-2a and (S)-2b obtained by our
method are enantiomerically pure, all the other planar-chiral
ferrocene derivatives in Scheme 5 are also single-enantiomeric,
i.e., we could have established the divergent process preparing a
library of various planar-chiral pyridine-based nucleophilic
organocatalysts in enantiomerically pure forms without chiral
resolution.
Table 2. Enantioselective Acetylation of rac-15 Catalyzed by
a
(S)-1
b
c
c
d
entry
(S)-1
conv (%)
% ee of 16
% ee of 15
s-factor
1
2
3
4
5
1bu
1bv
1bw
1bx
1by
65
62
66
70
60
41 (S)
43 (S)
41 (S)
39 (S)
40 (S)
75 (R)
70 (R)
78 (R)
92 (R)
61 (R)
5.0
5.0
5.3
6.7
4.2
a
The reaction was carried out in ether at 20 °C in the presence of
b
catalyst (S)-1 (4 mol %). Determined by 1H NMR analysis.
c
Determined by HPLC analysis on a chiral stationary phase (see the
Supporting Information for details). The absolute configurations of 16
and recovered 15 were determined by comparison with the reported
d
results [ref 4b]. Calculated based on a first-order equation [ref 22].
The library of (S)-1 was examined in the two prototypical
asymmetric reactions. The first one is the addition reaction of
2-tBu-phenol (13) to ethyl(p-tolyl)ketene (12),4i,21 and the
results are summarized in Table 1. With the exception of 1aw
(entry 3), all the other ferroco-pyridine derivatives showed good
catalytic activity for the reaction giving ester 14 in excellent
yields. The catalysts with an η5-C5H5 (1au, 1av, and 1aw) moiety
showed the modest enantioselectivity of 57% ee at most (entries
1−3). With the sterically more demanding Cp* ligand in place of
Cp in 1, the enantioselectivity was greatly improved ranging 79−
moderate enantioselectivity with the s-factors ranging 4.2−6.7.
The highest enantioselectivity was recorded with (S)-1bx (entry
4), which is the newly prepared species by the present study. This
is the clear-cut advantage of having the library of the asymmetric
catalysts.
In summary, we have established the synthesis of planar-chiral
ferrocene-fused 4-pyridone derivatives 2a and 2b both in
enantiomerically pure forms. Our synthetic method is scalable
and the single-enantiomeric pyridones could be obtained in a
multigram scale. Compounds 2 could be converted into various
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enantiomerically pure ferrocene-fused pyridine derivatives 1 via
enantioretentive transformations, and the library of the planar-
chiral pyridine-based nucleophilic organocatalysts could be
obtained.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compound characterization data, and
crystallographic data of (S)-(−)-2b (CIF file). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ogasawar@cat.hokudai.ac.jp.
*E-mail: ayanagi@faculty.chiba-u.jp.
*E-mail: tamotsu@cat.hokudai.ac.jp.
*E-mail: kyoshida@faculty.chiba-u.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Cooperative Research Program
from Catalysis Research Center, Hokkaido University (Grant
#11A0002), a Grant-in-Aid for Scientific Research on Innovative
Areas “Advanced Molecular Transformations by Organo-
catalysts” (Grant #24105502) from MEXT, Japan, and a
Grant-in-Aid for Young Scientists (B) (Grant #25810058)
from MEXT, Japan. We also gratefully acknowledge financial
support from the Uehara Memorial Foundation, the Naito
Foundation, and the next generation training program in Chiba
University.
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Org. Lett. 2015, 17, 2286−2289