Methanol-assisted catalysis by chiral tin methoxides: An alternative asymmetric aldol process

Article abstract of DOI:10.1002/chem.200901822

An alternative asymmetric aldol process was proposed for methanol-assisted catalysis by chiral tin methoxides. Binaphthol-based chiral organotin(IV) compounds were synthesized and alkenyl trichloroacetates were involved in the asymmetric aldol reaction, using the chiral tin compound as a catalyst generated in the presence of methanol. It was observed that the asymmetric aldol reaction proceeded through a chiral tin enolate according to a catalytic mechanism. The catalytic ability of the corresponding tin bromide methoxide generated from a 1:1 mixture chiral tin dibromide and MeONa in the aldol reaction of alkenyl trichloroacetate with pivalaldehyde was examined under optimized reaction conditions.

Full text of DOI:10.1002/chem.200901822

DOI: 10.1002/chem.200901822
Methanol-Assisted Catalysis by Chiral Tin Methoxides:
An Alternative Asymmetric Aldol Process
Akira Yanagisawa,* Tomoya Satou, Atsuto Izumiseki, Youichi Tanaka, Masahiko Miyagi,
Takayoshi Arai, and Kazuhiro Yoshida[a]
The catalytic asymmetric aldol reaction is one of the most
popular routes to nonracemic b-hydroxy carbonyl com-
pounds.[1] Numerous chiral catalysts have been designed and
prepared in an effort to develop an aldol process that has
superior stereoselectivity and chemical yield. Catalyst/nucle-
ophile combinations in catalytic systems are roughly classi-
fied into three types: 1) chiral Lewis acid/trialkylsilyl eno-
late system (Mukaiyama aldol type),[2] 2) chiral Lewis base/
trichlorosilyl enolate system,[3] and 3) chiral organocatalyst/
carbonyl compound system (direct aldol type).[4] However,
to the best of our knowledge, there are few examples of the
catalytic enantioselective aldol reaction via a chiral metal
Scheme 1. Proposed catalytic cycle for the aldol reaction of alkenyl tri-
chloroacetates with aldehydes catalyzed by Bu2SnACTHNUTRGEN(UNG OMe)2.
enolate.[5] We report here the synthesis of binaphthol-based
chiral organotin(IV) compounds and the asymmetric aldol
reaction of alkenyl trichloroacetates using the chiral tin
compound as a catalyst, which is regenerated in the pres-
ence of methanol. This asymmetric aldol reaction proceeds
via a chiral tin enolate according to a catalytic mechanism
that is different from those of the above-mentioned conven-
tional aldol processes.
target aldol product 4. The low rate of protonation of tin
enolate 2 with methanol compared to the rate of addition of
tin enolate 2 to aldehyde is the key to the successful catalyt-
ic reaction.
We envisioned that if a chiral tin dimethoxide, R*2Sn-
AHCTUNGRTEG(NNUN OMe)2, is used as a chiral catalyst in the present catalytic
We have previously found that dibutyltin dimethoxide
(Bu2SnACHTUNGTRENNUNG(OMe)2) catalyzes the aldol reaction between alkenyl
trichloroacetates and aldehydes including aliphatic alde-
hydes in the presence of MeOH.[6] The proposed catalytic
mechanism is shown in Scheme 1. First, alkenyl trichloroace-
system, an asymmetric version of the catalytic aldol reaction
might be possible in which nonracemic aldol product 7 or its
tin alkoxide 6 is formed via chiral tin enolate 5 (Scheme 2).
tate 1 reacts with Bu2SnACTHNUTRGNE(UNG OMe)2 to give tin enolate 2 and
methyl trichloroacetate. Then, an aldehyde is added to tin
enolate 2 to form tin alkoxide of aldol adduct 3. Finally, pro-
tonation of tin alkoxide 3 with methanol completes the cata-
lytic cycle and Bu2SnACHTNUGRTNE(NUG OMe)2 is regenerated together with
[a] Prof. Dr. A. Yanagisawa, T. Satou, A. Izumiseki, Dr. Y. Tanaka,
M. Miyagi, Dr. T. Arai, 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.200901822.
Scheme 2. Plausible catalytic cycle for the asymmetric version of the
aldol reaction.
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Chem. Eur. J. 2009, 15, 11450 – 11453

COMMUNICATION
As the chiral tin catalyst, we chose a binaphthol-derived
organotin compound as numerous chiral catalysts with a bi-
naphthyl structure have been developed and shown to be ef-
fective in various asymmetric reactions.[7] We first planned
to synthesize chiral tin dimethoxide 10 from (S)-BINOL (8).
According to the reported methods,[8] chiral tin dibromide 9
was prepared from 8 in 20% overall yield; however, we
failed to obtain the desired tin dimethoxide 10 by treatment
of tin dibromide 9 with two equivalents of sodium methox-
ide in methanol because of the low stability of 10
(Scheme 3).
3) trifluoromethanesulfonylation of 2,2’-OH groups, 4) Ni-
catalyzed cross-coupling reaction with methylmagnesium
bromide, 5) demethylation, and 6) trifluoromethanesulfony-
lation of 3,3’-OH groups produced 16 in 71% overall yield.
Ditriflate 16 underwent the Suzuki–Miyaura coupling with
4-tert-butylphenylboronic acid to provide coupling product
17 in 93% yield. Benzylic bromination (18,[10] 84% yield)
and subsequent oxidative addition by metallic tin (76%
yield) completed the synthesis of targeted tin dibromide 14.
With chiral tin dibromide 14 in hand, we examined the
catalytic ability of the corresponding tin bromide methoxide
generated from a 1:1 mixture of 14 and MeONa in the aldol
reaction of alkenyl trichloroacetate 12 with pivalaldehyde
under the optimized reaction conditions shown in Scheme 3.
Consequently, expected aldol adduct 13 was formed in 47%
yield with a syn/anti ratio of 90/10 through the reaction for
7 h. The level of asymmetric induction was approximately
90% ee (Table 1). In order to improve the chemical yield,
Table 1. Optimized conditions for the formation of aldol 13.
Scheme 3. Synthesis of aldol 13. Catalyst 10 (formed from 9 and MeONa;
x=20), yield: <1%. Catalyst 11 (formed from 9 and MeONa; x=10),
yield: 10%, syn/anti 78:22, ee=24% (syn).
Solvent
T [8C]
t [h]
Yield [%]
syn/anti
ee [%] (syn)
1
2
3
THF
THF
toluene
RT
40
40
7
2
1.5
47
65
70
90:10
97:3
94:6
87
86
85
Thus, we tried to generate 10 in situ and to use it directly
as a chiral catalyst in the aldol reaction of propiophenone-
derived alkenyl trichloroacetate 12 with pivalaldehyde at
room temperature for 7 h. Unfortunately, desired aldol
product 13 was not formed at all (Scheme 3). In contrast,
corresponding tin bromide methoxide 11, which was gener-
ated from an equimolar mixture of 9 and sodium methoxide
in MeOH, showed high reactivity and in fact, the reaction
gave 13 in 10% yield although the enantioselectivity of the
major syn isomer was low (Scheme 3).
As the latter reaction condi-
the reaction conditions were slightly modified and the
choice of a higher reaction temperature (408C) and/or tolu-
ene as solvent gave improved yields without significant loss
of enantioselectivity (Table 1).
tions were found to be favora-
ble, we attempted to synthesize
chiral tin dibromide 14 having a
4-tert-butylphenyl group at 3-
and 3’-positions, which is antici-
pated to be highly effective in
the asymmetric induction for
the present asymmetric aldol
reaction.[9] The total synthesis
of 14 from (S)-BINOL (8) is
shown in Scheme 4. Methoxy-
methyl ether (MOM) protec-
tion of 8 followed by a lithia-
tion–oxidation sequence gave
3,3’-dihydroxy BINOL deriva-
tive 15 in 88% overall yield
through three steps from 8. The
subsequent six-step transforma-
tion of 15 by 1) methylation, 2)
deprotection of MOM groups, Scheme 4. Synthesis of chiral tin dibromide 14.
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A. Yanagisawa et al.
Table 3. Catalytic asymmetric aldol reaction of cyclic alkenyl trichloroa-
cetates with aldehydes using chiral tin dibromide 14 and sodium methoxi-
de.[a]
The above result further prompted us to perform the
chiral-tin-catalyzed asymmetric aldol reaction of different
combinations of acyclic alkenyl trichloroacetates and alde-
hydes in toluene (Table 2). Treatment of 2-methyl-2-phenyl-
Table 2. Diastereo- and enantioselective aldol reaction of alkenyl tri-
chloroacetates with aldehydes using chiral tin dibromide 14 and sodium
methoxide.[a]
Alkenyl
trichloroacetate
R
Yield[b]
[%]
syn/
ee [%][d]
(syn, anti)
anti[c]
1
Ph
75
67:33
7, 11
Conditions Yield[b] syn/
ee [%][d]
ACHTUNGTNER(NUNG syn)
2
3
nC3H7
Me2CHCH2
99
95
47:53
51:49
90, 51
91, 58
X
R
[%]
anti[c]
1
2
3
4
5
6
7
H (12, E/Z=1:4) Me2PhC 408C, 4 h
80
80
65
75
41
63
54
95:5 93
>99:1 94
>99:1 97
85:15 98
89:11 99
96:4 88
99:1 95
Ph (E/Z=1:99)
Ph (E/Z=1:99)
Ph (E/Z=1:99)
Ph (E/Z=1:99)
iPr
tBu
RT, 18 h
RT, 16 h
[a] Unless otherwise specified, the reaction was carried out using chiral
tin dibromide 14 (10 mol%), sodium methoxide (10 mol%), alkenyl tri-
chloroacetate (2 equiv), and aldehyde (1 equiv) in THF at room tempera-
ture for 2–3 h. [b] Isolated yield. [c] Determined by 1H NMR analysis.
[d] Determined by HPLC analysis.
Me2PhC RT, 14 h
Me2PhC 08C, 30 h
MeO (E/Z=9:91) Me2PhC 408C, 4 h
Br (E/Z=1:4) tBu RT, 14 h
[a] Unless otherwise specified, the reaction was carried out using chiral
tin dibromide 14 (10 mol%), sodium methoxide (10 mol%), alkenyl tri-
chloroacetate (2 equiv), and aldehyde (1 equiv) in toluene under the
specified reaction conditions. [b] Isolated yield. [c] Determined by
1H NMR analysis. [d] The value corresponds to the syn isomer—deter-
mined by HPLC analysis.
afforded the syn product with more than 90% ee in the re-
action with the alkenyl trichloroacetate of 1-tetralone
though the syn/anti ratio of the products was almost 1:1 (en-
tries 2 and 3).[12]
In conclusion, we have developed a highly enantioselec-
tive method for the catalytic aldol reaction between alkenyl
trichloroacetates and aldehydes. The catalytic cycle via a
chiral tin enolate provides an alternative asymmetric aldol
process. This method is environmentally friendlier because
the amount of toxic organotin compounds is reduced to a
catalytic amount. Extensions of this catalytic system to
other asymmetric reactions are in progress.
propanal with propiophenone-derived alkenyl trichloroace-
tate 12 in the presence of chiral tin dibromide 14
(10 mol%), MeONa (10 mol%), and MeOH (10 equiv) in
dry toluene at 408C for 4 h gave a 95:5 mixture of optically
active syn and anti aldol adduct in 80% combined yield
(entry 1). The syn isomer showed 93% ee. The introduction
of a phenyl substituent to the para position of the alkenyl
trichloroacetate enabled the reaction to occur smoothly at a
lower temperature and in fact, approximately 70% yield of
the optically active aldol product was obtained syn-selective-
ly with 94–98% ee in the reaction with several aliphatic al-
dehydes (entries 2–4). The reaction with 2-methyl-2-phenyl-
propanal at 08C furnished an almost enantiomerically pure
product (entry 5). Satisfactory enantioselectivity was also
observed for a substrate with an electron-donating group
and one with an electron-withdrawing group (entries 6 and
7). However, use of aromatic aldehydes as acceptors result-
ed in low enantioselectivity.[11]
We then examined the chiral-tin-catalyzed aldol reaction
of cyclic alkenyl trichloroacetates with aldehydes (Table 3).
Addition of the cyclohexanone-derived alkenyl trichloroace-
tate to benzaldehyde produced the syn aldol adduct prefer-
entially with a syn/anti ratio of 67:33, contrary to the anti se-
lectivity shown by achiral tin methoxide-chiral silver catalyst
system.[6b–d] The syn isomer indicated a low enantiomeric
excess (entry 1). In the present asymmetric aldol reaction of
cyclic alkenyl trichloroacetates, aliphatic aldehydes are suit-
able electrophiles again to achieve a high level of asymmet-
ric induction. Indeed, butyraldehyde and 3-methylbutanal
Experimental Section
General experimental procedure for aldol reaction of aldehydes with al-
kenyl trichloroacetates catalyzed by chiral tin dibromide 14 (Tables 1 and
2): 1m MeONa in MeOH (50 mL, 0.05 mmol) and MeOH (0.15 mL) were
added to a solution of chiral tin dibromide 14 (41.2 mg, 0.05 mmol) in tol-
uene (3 mL) under argon atmosphere, and then the resulting mixture was
stirred at room temperature for 30 min. Subsequently, alkenyl trichloro-
acetate (1 mmol) and aldehyde (0.5 mmol) was added to the mixture at
this temperature. After being stirred for the specified time at room tem-
perature or 408C, the reaction mixture was treated with MeOH (1 mL),
brine (3 mL), and solid KF (ca. 0.5 g) at ambient temperature for 30 min.
The resulting precipitate was filtered off and the filtrate was dried over
Na2SO4 followed by concentration in vacuo. The residual crude product
was purified by column chromatography on silica gel to give a syn/anti
mixture of the corresponding aldol adduct. The syn/anti ratio was deter-
1
mined by H NMR and 13C NMR spectroscopy.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research on
Priority Area “Advanced Molecular Transformations of Carbon Resour-
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Chem. Eur. J. 2009, 15, 11450 – 11453

Asymmetric Catalysis
COMMUNICATION
ces” from the Ministry of Education, Culture, Sports, Science and Tech-
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3124.
Keywords: aldehydes
catalysis · enolates · tin
·
aldol reaction
·
asymmetric
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showed 14% ee.
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Received: July 2, 2009
Published online: September 25, 2009
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