Chiral anion catalysis in the enantioselective 1,4-reduction of the 1-benzopyrylium ion as a reactive intermediate

Article abstract of DOI:10.1002/chem.201302486

Anionic! Novel chiral anion catalysis of the enantioselective 1,4-reduction of the 1-benzopyrylium ion by a chiral phosphoric acid was accomplished with a Hantzsch ester as the reducing agent. The enantioselective reduction established is composed of a two-step consecutive transformation involving stereoablative loss of the hydroxy group from racemic 2H-chromen-2-ol derivatives to generate the achiral 1-benzopyrylium ion as a reactive key intermediate. Copyright

Full text of DOI:10.1002/chem.201302486

DOI: 10.1002/chem.201302486
Chiral Anion Catalysis in the Enantioselective 1,4-Reduction of the 1-
Benzopyrylium Ion as a Reactive Intermediate
Masahiro Terada,*[a, b] Takuto Yamanaka,[a] and Yasunori Toda[a]
The 1-benzopyrylium ion is an inherently stable and isola-
ble cationic species due to the aromaticity of its ten p-elec-
tron system, and it is known as a reactive intermediate in
synthetic organic chemistry.[1] However, little attention has
been devoted to the utilization of this reactive, and hence
attractive, intermediate in enantioselective transformations.
In fact, only a few enantioselective catalytic protocols have
exploited the 1-benzopyrylium ion as the reactive intermedi-
ate,[2] despite the fact that the method provides efficient
access to chroman derivatives in an optically active form.
The chroman skeleton constitutes an important structural
motif in natural products with ubiquitous occurrence, and
also appears as a key structural element in many biologically
active compounds.[3] Hence, the preparation of a single
enantiomer of these derivatives by enantioselective catalysis
is an attractive methodology that allows the asymmetric syn-
thesis of the chroman motif in a very simple and efficient
manner.[2,4] In this context, we envisioned the development
of an enantioselective transformation involving the in-situ
generation of the 1-benzopyrylium ion as the reactive inter-
mediate under chiral Brønsted acid catalysts.
ated in situ from racemic 2H-chromen-2-ol (2) under the in-
fluence of chiral phosphoric acid 1 (Figure 1). In this trans-
formation, the contact ion pair formed between 1-benzo-
pyrylium ion A and chiral conjugate base 1À of phosphoric
Chiral Brønsted acids,[5] in particular binaphthol-derived
phosphoric acids 1,[6] have emerged as powerful tools for
enantioselective transformations, and significant progress
has been made in their utilization as chirality-inducing
agents since the initial reports by Akiyama et al. and our
group in 2004.[7] Among the protocols exploited, chiral
anion catalysis[8] has received much attention in recent years
due to its potential for broadening the scope of chiral
Brønsted acid catalysis.[9] The 1-benzopyrylium ion is, hence,
an attractive target for enabling the further cultivation of
chiral anion catalysis by chiral phosphoric acids 1. In this
regard, we sought to develop an unprecedented enantiose-
lective transformation of the 1-benzopyrylium ion A, gener-
Figure 1. Chiral anion catalysis of the enantioselective reduction of 1-
benzopyrylium ion.
acid 1 reacts with a nucleophile within the chiral environ-
ment created by the chiral conjugate base 1À. Herein, we
report the novel enantioselective reduction of the 1-benzo-
pyrylium ion A[10] with the Hantzsch ester 3 as the nucleo-
philic agent.[11] Chiral anion catalysis gives rise to the 1,4-re-
duction product exclusively, yielding the 4H-chromene de-
rivative 4 in a highly enantioselective manner. The catalytic
reaction proceeds through stereoablative[12] loss of the hy-
droxy group from racemic 2 to generate the achiral inter-
mediate 1-benzopyrylium ion A, followed by construction of
a new stereogenic center at the 4-position through enantio-
selective 1,4-reduction of achiral A under chiral anion catal-
ysis. In the established system, a racemic mixture of 2H-
chromenol 2 is efficiently converted to an enantioenriched
4H-chromene derivative 4 in an enantio-convergent process
mediated by chiral phosphoric acid 1.
[a] Prof. Dr. M. Terada, T. Yamanaka, Dr. Y. Toda
Department of Chemistry
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
Fax : (+81)22-795-6584
E-mail: mterada@m.tohoku.ac.jp
[b] Prof. Dr. M. Terada
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
At the outset of our studies on chiral anion catalysis, 6-
methyl substituted 2,4-diphenyl-2H-chromen-2-ol 2a was
employed as an initial substrate for the precursor of the 1-
benzopyrylium ion. The reaction was conducted with chro-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302486.
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Chem. Eur. J. 2013, 19, 13658 – 13662

COMMUNICATION
menol 2a, 5 mol% of the chiral phosphoric acid 1,[13] and
1.2 equiv of the allyl ester 3[14] in toluene at room tempera-
ture for 1 h. As shown in Table 1, entry 1, the reaction pro-
ceeded smoothly to afford the 4H-chromene 4a in a good
(Table 1, entry 5). When a methoxy group was introduced in
the 7-position, a significant reduction in enantioselectivity
was observed. As expected, the enantiomeric excess in-
creased with decreasing reaction temperature, reaching 87%
ee at À208C (Table 1, entry 6). However, further reduction
of the reaction temperature to À358C led to a disappointing
stereochemical outcome (Table 1, entry 7).[17]
Table 1. Initial screening of the reaction conditions.[a]
The effect of the chromenol core substituent prompted us
to further screen oxygenated substituents at the 6-position
of chromenol 2 (Table 1, entries 8–13). Subsequent manipu-
lation of the oxygenated substituents had a strong impact on
the stereochemical outcome. Protection of the 6-hydroxy
moiety with either a methoxymethyl (MOM) group (2 f) or
a tert-butoxycarbonyl (Boc) group (2g) led to a considerable
decrease in the enantioselectivity (Table 1, entries 8 and 9).
Whereas substitution with benzyl ether (2h) at the 6-posi-
tion slightly compromised the enantioselectivity (Table 1,
entry 10), ethyl ether (2i) enhanced the selectivity to 90%
ee (Table 1, entry 11). Further improvement in the enantio-
selectivity was achieved with the introduction of sterically
hindered substituents, such as isopropyl ether (2j) and tert-
butyl ether (2k). Enantioselectivities as high as 93% ee
were obtained for these derivatives (Table 1, entries 12 and
13). Considering the ease of removal of the protective group
of the 6-hydroxy moiety, the tert-butyl ether group was em-
ployed for subsequent investigations.
Having identified the optimal protective group for chro-
menol 2 as tert-butyl ether and the optimized reaction condi-
tions, we further investigated the enantioselective reduction
of a range of chromenols 2.[18] Table 2 summarizes the ex-
periments carried out to probe the substrate scope of the
present chiral anion catalysis reaction. In all cases, the re-
duction products 4 were obtained in good to excellent chem-
ical yields, irrespective of the electronic and steric properties
of the aromatic substituents (Ar1 and Ar2). Investigation of
the substituent effect of the Ar1 moiety indicated that Ar1
substituents with either electron-withdrawing or -donating
groups (Table 2, entries 1 and 2) led to a slight reduction in
the enantioselectivity. In addition, the enantioselectivities
were slightly dependent on the Ar2 moiety (Table 2, en-
tries 3–6), however, the highest enantioselectivity was ob-
served in the reaction of 4p bearing a p-methoxyphenyl
group (Table 2, entry 5). Introduction of an ortho substitu-
ent in the Ar2 moiety, however, led to a considerable reduc-
tion in the enantioselectivity with quantitative formation of
the 4H-chromene derivative 4r (Table 2, entry 7). A slight
reduction in the enantioselectivity was also observed in the
reaction of chromenol 2s with electron-donating groups in
both the Ar1 and Ar2 moieties (Table 2, entry 8). However,
in this case, the stereochemical outcome could be improved
by lowering the reaction temperature to À358C (Table 2,
entry 9).[17]
Entry
2
4
Yield [%][b]
ee [%])[c]
1
2
3
4
2a: X=6-Me
2b: X=H
2c: X=6-Br
2d: X=6-MeO
2e: X=7-MeO
2d
4a
4b
4c
4d
4e
4d
4d
4 f
4g
4h
4i
91
90
87
89
99
98
97
83
>99
98
58
43
47
72
19
87
85
41
57
84
90
93
93
5
6[d]
7[e]
8[d]
9[d]
10[d]
11[d]
12[d]
13[d]
2d
2 f: X=6-MOMO
2g: X=6-BocO
2h: X=6-BnO
2i: X=6-EtO
2j: X=6-iPrO
2k: X=6-tBuO
>99
95
91
4j
4k
[a] Unless otherwise noted, all reactions were carried out with
0.005 mmol of (R)-1 (5 mol%), 0.1 mmol of 2, and 0.12 mmol of 3
(1.2 equiv) in toluene (0.5 mL) at room temperature for 1 h. [b] Isolated
yield of 4. [c] The enantiomeric excess of 4 was determined by chiral sta-
tionary phase HPLC analysis. The absolute configuration at the 4-posi-
tion of 4 was assigned to be (R) by analogy. See Table 2, entry 3 and the
Supporting Information for details. [d] At À208C for 24 h. [e] With
0.01 mmol of (R)-1 (10 mol%) at À358C for 24 h.
yield with moderate enantioselectivity. The exclusive forma-
tion of the 4H-chromene regio-isomer is of particular inter-
est. Neither the 2H-chromene nor ring-opened by-products
were observed. The regio-selectivity observed is in contrast
to that found for typical nucleophilic additions to 1-benzo-
pyrylium ions bearing a substituent at the 4-position.[2a,15]
The formation of 2H-chromene derivatives, in most
cases,[2b–d,16] although it markedly depends on the substituent
pattern, is well-documented.[15] Encouraged by this prelimi-
nary result, we investigated the effect of substituents on the
chromenol core (Table 1, entries 2–4). The substituents in-
troduced to the chromenol core had a marked effect on the
enantioselectivity. Whereas removal of the methyl substitu-
ent from the 6-position, giving 2b, or introduction of a bro-
mide, giving 2c, led to a slight decrease in the enantioselec-
tivity (Table 1, entries 2 and 3), the reaction of chromenol
2d with a methoxy substituent resulted in a noticeable in-
crease in the stereoselectivity (Table 1, entry 4). It is note-
worthy that the positional effect on enantioselectivity of the
substituent introduced to the chromenol core was significant
To shed light on the reaction mechanism, we confirmed
the formation of 1-benzopyrylium ion A by UV/Vis spectro-
scopic analysis (the UV/Vis absorbance of 1-benzopyrylium
species has been reported to appear at 400–600 nm).[20]
Indeed, a pale yellow solution of chromenol 2k in toluene
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M. Terada et al.
Table 2. Substrate scope for the enantioselective reduction.[a]
selectivity observed by the reduction of 2k does not change
in either presence or absence of MS 4 ꢁ. It is noteworthy
that the enantioselectivity was dependent on the starting
chromene derivatives. The chromene derivative 5 having iso-
propoxy moiety as the leaving group exhibited a remarkable
decrease in the enantioselectivity (78% ee). More interest-
ingly, enantioselectivity of 4k obtained by the partial reduc-
tion of 5 with 0.3 equiv of 3 (68% ee) was lower than that of
the complete reduction of the racemic mixture 5 (78% ee).
The observed difference in the enantioselectivity between
the initial and final stages presumably suggests that the
chiral information of racemic 5, unfavourable for the pres-
ent enantio-convergent process, is partially maintained
during the course of the enantioselective reduction.[17] In
sharp contrast, the enantioselective reduction of chromen-2-
ol 2k having hydroxy moiety as the leaving group exhibited
the same enantioselectivity at the initial (93% ee) and final
(93% ee) stages. These results can be demonstrate that the
reaction proceeded through complete loss of racemic chiral
information, when a hydroxy moiety was employed as the
leaving group. Although the precise mechanism of the ste-
reochemical outcome has not yet been clarified, it seems
that the reaction proceeds through formation of a contact
ion pair between the 1-benzopyrylium ion and the chiral
conjugate base of phosphoric acid (R)-1, as postulated in
Figure 1.
Entry
4
Ar1
Ar2
Yield [%][b]
ee [%][c]
1
2
3
4
5
4l:
p-FC6H4
p-MeOC6H4
Ph
Ph
Ph
Ph
Ph
89
95
95
94
98
87
4m:
4n:
4o:
4p:
91
p-ClC6H4
p-MeC6H4
p-MeOC6H4
93[d]
90
96
6
4q:
Ph
85
89
7
4r:
4s:
4s
Ph
o-MeOC6H4
p-MeOC6H4
>99
97
97
74[e]
80
86
8
p-MeOC6H4
9[f]
[a] Unless otherwise noted, all reactions were carried out with
0.005 mmol of (R)-1 (5 mol%), 0.1 mmol of 2, and 0.12 mmol of 3
(1.2 equiv) in toluene (0.5 mL) at À208C for 24 h. [b] Isolated yield of 4.
[c] The enantiomeric excess of 4 was determined by chiral stationary
phase HPLC analysis. The absolute configuration at the 4-position of 4
was assigned to be (R) by analogy. [d] The absolute configuration at the
4-position of 4n was determined to be (R) by X-ray crystallographic anal-
ysis.[19] See the Supporting Information for details. [e] The enantiomeric
excess of 4r was determined after derivatization to chroman-3-ol deriva-
tive 6b in accordance with the similar method depicted in Scheme 2.
[f] With 0.01 mmol of (R)-1 (10 mol%) at À358C.
Finally, we attempted the further derivatization of the op-
tically active chromene 4k thus obtained. As shown in
Scheme 2, 4k was readily and quantitatively transformed to
immediately turned to an orange color upon addition of
a stoichiometric amount of phosphoric acid 1. UV/Vis spec-
troscopic analysis of the resultant orange solution exhibited
a distinct peak at 414 nm, clearly indicating the formation of
the 1-benzopyrylium ion.
Further mechanistic investigation was performed by
changing the leaving group (OR1) of the starting chromene
derivative from hydroxy moiety, 2k, to isopropoxy moiety, 5
(Scheme 1). The reaction of racemic isopropoxy chromene
derivative 5 was conducted under the optimized reaction
conditions (À208C, 24 h) in the presence of molecular sieves
(MS) 4 ꢁ which were employed to suppress the influence of
adventitious water. It has been confirmed that the enantio-
Scheme 2. Derivatization of chromene 4k to chroman-3-ol 6a: a)
BH3·THF (3 equiv), THF (0.2m), 08C, 22 h then b) 30% H2O2 aq.
(9 equiv), 5% NaOH aq. (ca. 4 equiv), THF (0.06m), 608C, 15 h, 99%
over 2 steps.
chroman-3-ol derivative 6a by the standard hydroboration/
oxidation procedure in high diastereofacial selectivity with-
out loss of the enantiomeric purity. The present catalytic
method thus enables facile access to 4H-chromenes 4 and
further derivatives such as chroman-3-ols 6, which are
a ubiquitous structural motif found in plant phenolics such
as flavonoids,[21] in their optically active form.
In conclusion, we have demonstrated a novel chiral anion
catalysis for the enantioselective reduction of the 1-benzo-
pyrylium ion mediated by a chiral phosphoric acid. In con-
trast to well-documented nucleophilic additions to 1-benzo-
pyrylium ions, in which 2H-chromene derivatives are
formed in most cases, the present enantioselective reduction
gives rise to 4H-chromene derivatives exclusively. The pres-
ent method not only facilitates enantioselective formation of
4H-chromene derivatives from racemic 2H-chromenols by
Scheme 1. Effect of leaving group (OR1).
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Enantioselective 1,4-Reduction of 1-Benzopyrylium Ions
COMMUNICATION
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Experimental Section
To a dried test tube was added 2k (37.3 mg, 0.10 mmol). Compound 2k
was dissolved in toluene (0.5 mL) and the solution was cooled to À208C.
To the solution were added (R)-1 (5 mol%, 3.76 mg, 0.005 mmol) and 3
(33.3 mg, 0.12 mmol) at À208C. The mixture was stirred for 24 h at
À208C. The reaction mixture was quenched with NEt3 at À208C. After
warming to room temperature, the mixture was poured into saturated
aqueous NaHCO3, and then extracted with CH2Cl2 (ꢂ3). The combined
organic layers were dried over Na2SO4, filtered, and concentrated. After
purification by flash column chromatography on silica gel (only CH2Cl2),
4k was obtained in 91% yield as a white solid (93% ee). The enantio-
meric excess was determined by chiral stationary phase HPLC analysis.
Acknowledgements
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This work was partially supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas “Advanced Molecular Transformations by
Organocatalysts” from MEXT, Japan and a Grant-in-Aid for Scientific
Research (Grant No. 20245021) from the JSPS. We gratefully acknowl-
edge Prof. T. Ooi and Prof. D. Uraguchi (Nagoya University), Dr. J.
Takehara and Dr. T. Sudo (Mitsubishi Chemical Co., Ltd.), and Dr. Y.
Nakamura and Mr. T. Takeda (Daiichi Sankyo Co., Ltd.) for the HRMS
analysis. We also thank the JSPS for a research fellowship for Young Sci-
entists (Y.T.).
Keywords: asymmetric catalysis · benzopyrylium · Brønsted
acids · enantioselective reduction · organocatalysis
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[18] Starting chromenols having an aliphatic substituent at the 2- or 4-
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[13] See the Supporting Information for screening of other chiral phos-
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[14] See the Supporting Information for the screening of other Hantzsch
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[19] CCDC-904316 [(R)-4n)] contains the supplementary crystallograph-
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Received: June 27, 2013
Published online: September 17, 2013
13662
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