Enantioselective protonation of alkenyl trifluoroacetates catalyzed by chiral tin methoxide

Article abstract of DOI:10.1002/chem.201302975

Go catalytic! A catalytic enantioselective protonation of alkenyl trifluoroacetates was achieved by using an in situ generated chiral tin bromide methoxide as the chiral catalyst in the presence of methanol (see scheme). Optically active ketones containing a tertiary stereogenic center at the α-position were obtained with enantioselectivities of up to 94 % ee. Copyright

Full text of DOI:10.1002/chem.201302975

DOI: 10.1002/chem.201302975
Enantioselective Protonation of Alkenyl Trifluoroacetates Catalyzed by
Chiral Tin Methoxide
Akira Yanagisawa,* Takuya Sugita, and Kazuhiro Yoshida[a]
Carbonyl compounds possessing a tertiary carbon atom at
their a-position are often encountered in natural products
or biologically active molecules. One of the promising ways
to acquire such compounds in an enantioselective fashion is
the asymmetric protonation of enolates, enols, enol ethers,
or enol esters.[1–4] For the transformation, various chiral cata-
lysts, including chiral Brønsted acid catalysts and chiral
Lewis acid catalysts, are available. In contrast, examples of
transformations employing chiral base catalysts are few. We
have previously reported a method for preparing chiral tin
methoxide catalysts, which uses sodium methoxide and the
corresponding chiral tin dibromides bearing a 3,3’-substitut-
ed binaphthyl moiety.[5a] The in situ generated chiral tin
methoxides are efficiently transformed into chiral tin eno-
lates in the reaction with alkenyl trichloroacetates. The thus-
obtained chiral tin enolates show adequate nucleophilicity
toward various electrophiles and undergo asymmetric trans-
formations, including the aldol reaction,[5] the Mannich-type
reaction,[6] 1,3-dipolar cycloaddition,[7] g-lactone synthesis,[8]
and the N-nitroso aldol reaction.[9] We envisioned that if
a prochiral alkenyl ester derived from a ketone containing
a tertiary carbon atom at the a-position were used as the
substrate for the chiral tin catalysis in the presence of an al-
cohol, the asymmetric protonation of an in situ generated
chiral tin enolate would be possible. We report herein, the
enantioselective protonation of cyclic alkenyl trifluoroace-
tates with methanol by using chiral tin dibromide and
sodium methoxide as precatalysts (Scheme 1).
We initially adopted a 2-methyl-1-tetralone-derived alken-
yl trichloroacetate as the substrate for the protonation and
optimized the reaction conditions. As a result, when the al-
kenyl trichloroacetate was treated with chiral tin dibromide
1a (10 mol%) and NaOMe (10 mol%) in the presence of
MeOH (40 equiv) in hexane at room temperature for 46 h,
(S)-enriched 2-methyl-1-tetralone with 87% enantiomeric
excess (ee) was obtained in 42% yield (Scheme 2). We then
Scheme 2. Optimization of alkenyl esters.
examined the ability of alkenyl trifluoroacetates to generate
chiral tin enolates. Alkenyl esters have been shown to be su-
perior substrates for the enantioselective protonation em-
ploying a cinchona alkaloid as the chiral catalyst.[3r,10] We at-
tempted the asymmetric protonation of a 2-methyl-1-tetra-
lone-derived alkenyl trifluoroacetate and, as a consequence,
obtained the targeted ketone in a satisfactory yield with im-
proved enantiomeric excess in the reaction for 1 h
(Scheme 2).
Accordingly, we optimized the reaction conditions by
using the alkenyl trifluoroacetate. The results are summar-
ized in Table 1. Reducing the amounts of the pre-catalysts
to 2 mol% did not cause a significant deceleration of the re-
action (compare entries 2 and 1, Table 1). To obtain a prod-
uct with a higher enantiomeric ratio, we elevated the reac-
tion temperature. The reaction at 508C increased the enan-
tioselectivity to 93% ee (entry 5).
Scheme 1. Enantioselective protonation of cyclic alkenyl trifluoroacetates
catalyzed by in situ generated chiral tin methoxide.
We further examined the effects of substituents at 3,3’-po-
sitions of chiral tin precatalyst 1. When Ph-substituted chiral
tin dibromide 1c was used, the protonation proceeded and
both yield and enantiomeric excess were higher than those
obtained by using chiral tin dibromide 1a, which has 4-
F3CC6H4 groups at its 3,3’-positions (Table 2, compare en-
tries 3 and 1). Because the employment of 3,3’-unsubstituted
chiral tin precatalyst 1e (Ar=H) resulted in a low enantio-
meric excess (entry 4), bulky substituents at the 3,3’-posi-
[a] Prof. Dr. A. Yanagisawa, T. Sugita, Prof.Dr. K. Yoshida
Department of Chemistry, Graduate School of Science
Chiba University, Inage, Chiba 263-8522 (Japan)
Fax : (+81)43-290-2789
E-mail: ayanagi@faculty.chiba-u.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302975.
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COMMUNICATION
Table 1. Optimization of reaction conditions.[a]
Table 3. Asymmetric protonation of various alkenyl trifluoroacetates.[a]
Entry
x [mol%]
T [8C]
Yield [%][b]
ee [%][c]
Entry
X
R1
(CH2)2 Me
(CH2)2 Et
(CH2)2 Allyl
(CH2)2 Bn
(CH2)2 Bn
(CH2)2 Me
(CH2)2 Me
(CH2)2 Me
R2
Chiral tin Yield [%][b] ee [%][c]
1
2
3
4
5
10
2
2
2
2
RT
RT
30
40
50
80
77
87
82
82
91
91
90
92
93
1
2
3
4
5
6
7
A
H
H
H
H
H
6-MeO
6-MeO
7-MeO
H
H
H
H
H
H
H
H
1c
1c
1c
1c
1a
1c
1a
1c
1c
1a
1c
1a
1c
1a
1c
1c
94
86
92
43
91
88
90
97
82
92
71
85
93
>99
83
94
94
94
94
69
92
93
83
93
80
70
79
85
63
64
81
69
N
N
R
E
T
[a] Unless otherwise specified, the reaction was carried out by using
chiral tin dibromide 1a (x mol%), sodium methoxide (x mol%), alkenyl
trifluoroacetate (1 equiv), and methanol (40 equiv) in hexane. [b] Isolated
yield. [c] Determined by HPLC analysis.
R
8[d]
9
T
CH2
CH2
CH2
CH2
CH2
CH2
OCH2
OCH2
Me
Me
Et
Et
nC8H17
nC8H17
Me
10
11
12
13[e]
14[e]
15[f]
16[f]
Table 2. Asymmetric protonation by using various chiral tin catalysts.[a]
Bn
[a] Unless otherwise specified, the reaction was carried out by using
chiral tin dibromide 1a or 1c (2 mol%), sodium methoxide (2 mol%), al-
kenyl trifluoroacetate (1 equiv), and methanol (40 equiv) in hexane at
508C for 1 h. [b] Isolated yield. [c] Determined by HPLC analysis.
[d] The reaction was performed for 2 h. [e] The reaction was performed
at 608C. [f] The reaction was performed for 3 h.
Entry
Chiral tin
Yield [%][b]
ee [%][c]
toward a chiral tin methoxide under conventional reaction
conditions, although their asymmetric induction was moder-
ate (entries 9–14). In general, chiral tin dibromide 1a was
a more suitable precatalyst than 1c for the substrates to ac-
quire high chemical yields (compare entries 10, 12, and 14
with entries 9, 11, and 13). 4-Chromanone derivatives could
be also applied to this asymmetric protonation and in fact,
nonracemic 3-alkyl-4-chromanones were efficiently obtained
by this method (entries 15 and 16).
1
2
3
4
5
1a
1b
1c
1d
1e
82
>99
94
80
98
93
88
94
92
65
[a] Unless otherwise specified, the reaction was carried out by using
chiral tin dibromide 1 (2 mol%), sodium methoxide (2 mol%), alkenyl
trifluoroacetate (1 equiv), and methanol (40 equiv) in hexane at 508C for
1 h. [b] Isolated yield. [c] Determined by HPLC analysis.
To derive useful information about the structure of an in
situ generated chiral tin bromide methoxide in solution, we
investigated the nonlinear effect of the asymmetric protona-
tion. We prepared chiral tin dibromide 1c containing various
optical purities (100, 80, 50, 20, and 0% ee) and carried out
the reaction of 6-methoxy-2-methyl-1-tetralone-derived al-
kenyl trifluoroacetate by using 1c of diverse enantiomeric
excesses in hexane at 508C for 1 h. As a result, a positive
nonlinear effect between the enantiomeric excess of 1c and
that of the product was clearly observed (Figure 1). In par-
ticular, in the case of the catalyst possessing 20% ee, a 2.5-
fold amplification of the enantiomeric excess was observed.
Judging from the above-mentioned results on the nonlin-
ear effect, chiral tin bromide methoxide catalysts are consid-
ered to exist in equilibrium among homochiral dimers
((S,S)- and (R,R)-dimer), monomers ((S)- and (R)-mono-
mer), and a heterochiral dimer ((S,R)-dimer). An example
of a chiral tin bromide methoxide derived from 1c (Ar=
Ph) is shown in Figure 2. To realize the positive nonlinear
relationship between the enantiomeric excess of 1c and that
of the product, the (S)- and (R)-monomer should be the
tions were found to be effective in attaining a high level of
asymmetric induction in the protonation.
With the optimal reaction conditions in hand, we studied
the catalytic enantioselective protonation of numerous al-
kenyl trifluoroacetates. The results obtained with 2-methyl-
1-tetralone and related cyclic ketone derivatives are shown
in Table 3. Both the 2-ethyl and the 2-allyl derivatives pro-
vided high optical purities identical with that of 2-methyl-1-
tetralone (entries 1–3, Table 3). In contrast, the reaction of
the 2-benzyl derivative led to an unsatisfactory chemical
yield and enantiomeric excess, probably due to the steric
bulkiness of the substituent. However, use of more Lewis
acidic chiral tin precatalyst 1a in place of 1c with the same
alkenyl trifluoroacetate gave an isolated yield and an enan-
tiomeric excess of more than 90% (entries 4 and 5). The ex-
istence of an electron-donating group on the aromatic ring
did not have a significant influence on the reactivity of the
substrates (entries 6–8). Alkenyl trifluoroacetates of 2-alkyl-
1-indanones were also preferable substrates for the present
asymmetric protonation; they exhibited sufficient reactivity
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A. Yanagisawa et al.
Figure 3. Plausible catalytic cycle for the asymmetric protonation.
Figure 4. A hypothesis for enantioface discrimination between a chiral
tin enolate and methanol.
A hypothesis for the enantioface discrimination between
a chiral tin enolate and methanol in the present enantiose-
lective protonation catalyzed by a chiral tin bromide meth-
oxide is shown in Figure 4.
Figure 1. Positive nonlinear effect of the asymmetric protonation.
Methanol approaches the a-
carbon atom of a chiral tin eno-
late to escape from steric hin-
drance caused by phenyl groups
at the 3,3’-positions of the bi-
naphthyl framework. Conse-
quently, protonation occurs se-
lectively at the Re face of the
tin enolate to furnish the (S)-
ketone.
In conclusion, we have devel-
oped a novel catalytic asymmet-
ric protonation. The employ-
ment of in situ generated chiral
tin bromide methoxide as the
Figure 2. Equilibrium among homochiral dimers, monomers, and a heterochiral dimer (Ar=Ph).
most reactive and the (S,R)-dimer should be the least reac-
tive in the equilibration.
chiral catalyst and MeOH as the proton source allows the
synthesis of various optically active ketones containing a ter-
tiary stereogenic center at the a-position, with an enantiose-
lectivity of up to 94% ee. Further studies of the application
of the catalytic asymmetric protonation to other substrates
are underway.
A catalytic cycle is postulated for the asymmetric proto-
nation (Figure 3). First, chiral tin dibromide 1a or 1c reacts
with an equimolar amount of sodium methoxide to afford
the corresponding chiral tin bromide methoxide, which is
the real catalyst in the present transformation. Subsequently,
the generated chiral tin bromide methoxide attacks alkenyl
trifluoroacetate 2 to form chiral tin enolate 3 and methyl tri-
fluoroacetate (4). The following protonation with methanol
gives optically active ketone 5 with regeneration of the
chiral tin bromide methoxide. The rate of methanolysis of
tin enolate 3 plays an important role in the catalytic cycle.
Experimental Section
General experimental procedure for catalytic asymmetric protonation of
alkenyl trifluoroacetates (Tables 2 and 3): NaOMe (1m) in MeOH
(10 mL, 0.01 mmol) and MeOH (0.8 mL) were added to a suspension of
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Enantioselective Protonation of Alkenyl Trifluoroacetates
COMMUNICATION
chiral tin dibromide 1 (0.01 mmol) in hexane (3 mL) under an argon at-
mosphere, and then the resulting mixture was stirred at room tempera-
ture for 30 min. Subsequently, alkenyl trifluoroacetate (0.5 mmol) was
added to the mixture at this temperature. After the mixture had been
stirred for 1 h at 508C, the reaction mixture was treated with brine
(2 mL) and solid KF (ca. 1 g) at ambient temperature for 3 min. The re-
sulting precipitate was filtered off and the filtrate was extracted with
ether (15 mL) three times. The combined organic extracts were dried
over Na2SO4 and concentrated in vacuo after filtration. The residual
crude product was purified by column chromatography on silica gel to
give the corresponding ketone. The enantioselectivity was determined by
HPLC analysis by using a chiral column.
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Acknowledgements
We gratefully acknowledge the financial support from the Iodine Re-
search Project in Chiba University led by Prof. H. Togo and the COE
Start-up Program in Chiba University led by Prof. Takayoshi Arai.
Keywords: alkenyl esters · asymmetric catalysis · ketones ·
protonation · tin
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Received: July 29, 2013
Published online: October 31, 2013
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